Ethenyl and ethynyl mercaptoalkyl pyridines

ABSTRACT

Mercaptoalkylpyridines carrying an ethenyl or ethynyl substituent are prepared from known pyridine compounds, principally pyridoxine, by known chemical procedures, and are useful in the treatment of rheumatoid arthritis and related inflammatory diseases.

This is a division of application Ser. No. 578,692, filed, May 19, 1975,now abandoned, which in turn is a continuation-in-part of co-pendingapplication Ser. No. 464,011, filed Apr. 26, 1974, now abandoned, whichin turn is a continuation-in-part of application Ser. No. 368,772, filedJune 15, 1973, now abandoned.

This invention is concerned with novel mercaptoalkylpyridines andderivatives thereof carrying a nuclear unsaturated substituent, methodsfor their preparation, a method of treating rheumatoid arthritis andrelated inflammatory diseases with the novel compounds andpharmaceutical compositions containing these novel compounds as activeingredient.

More particularly, the invention is concerned with novel compounds ofstructural formula: ##STR1## OR PHARMACEUTICALLY ACCEPTABLE SALTTHEREOF, WHEREIN

M IS 0 OR 1;

X is an integer from 0-3;

A is ##STR2## or --C.tbd.C--; where

R⁷ is hydrogen, chloro, or fluoro;

R¹ and R² are hydrogen or C₁₋₃ alkyl;

R³ is (a) hydrogen, (b) -SO₃ H, (c) -PO₃ H₂, (d) amidino, (e) N(C₁₋₄alkyl), (f) -CH₂ CH(NH₂)COOH, (g) ethoxycarbonylmethyl, ##STR3## WHERE Erepresents (1) adamantyl, (2) C₃₋₈ cycloalkyl, (3) C₁₋₅ alkoxy, (4) C₂₋₆alkyl, (5) N(C₁₋₄ alkyl)₂, (6) phenyl, (7) 2-acetoxyphenyl, (8)2-hydroxy-4-(2,4-difluorophenyl)phenyl, (9) 3-chloro-4-allyloxybenzyl,(10) α-methyl-4-isobutylbenzyl, (11) α-methyl-3-phenoxybenzyl, (12)α-methyl-3-benzoylbenzyl, (13) 1-(6-methoxynaphth-2-yl)ethyl, (14)α-methyl-3-fluoro-4-phenylbenzyl, (15)2-(3-chloro-4-cyclohexylbenzoyl)ethyl, (16)2-(3-trifluoromethylanilino)phenyl, (17) 2-(2,3-dimethylanilino)phenyl,(18) 2-(2,6-dichloro-3-methylanilino)phenyl, (19)2-(3-trifluoromethylanilino-3-pyridyl, (20)2-(2-methyl-3-chloroanilino)-3-pyridyl, or ##STR4## where G represents(1) C₁₋₄ alkoxy, (2) -S(alkali metal) or ##STR5## wherein L represents(1) -(CH₂)₁₋₅ -, (2) phenylene, or ##STR6## (m) -S-R⁸, wherein R⁸represents (1) -C(CH₃)₂ CH(NH₂)COOH, (2) C₁₋₅ alkyl, (3) C₂₋₅ alkenyl,(4) phenyl-C₁₋₃ alkyl, (5) phenyl, (6) C₂₋₅ alkynyl, (7)2-carboxyphenyl, or ##STR7## R⁴ is hydrogen, C₁₋₃ alkyl, phenyl, chloro,carboxy, C₁₋₃ alkoxycarbonyl, fluoro; and R is (a) C₁₋₃ alkyl, (b)hydroxy, ##STR8## (d) hydroxy-C₁₋₃ alkyl; and (e) when one R is hydroxyadjacent to the ##STR9## group the oxygen and sulfur thereof may bejoined together through a group of formula: ##STR10## wherein R⁵ andR.sub.α⁵ are the same or different and each is hydrogen, C₁₋₆ alkyl,phenyl, dimethylphenyl, or difluorofluorophenyl, or taken together, R⁵and R.sub.α⁵ represent ═O or ═S.

A preferred embodiment of this invention is the compound described abovewherein the -AR⁴ group and the ##STR11## group are alternatively in the4 and 5-positions of the pyridine ring, X = 2.

A still more preferred embodiment is the compound of structural formula:##STR12## and especially wherein A-R⁴ represents -CH═CH₂, R representshydroxy or C₂₋₆ alkanoyloxy, and R³ represents hydrogen, --SO₃ H, C₂₋₆alkanoyl, or ##STR13## or a pharmaceutically acceptable salt thereof.

Of particular importance are the compounds:

2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine;

2-methyl-3-acetoxy-4-acetylthiomethyl-5-vinylpyridine;

2-methyl-3-hydroxy-4-acetylthiomethyl-5-vinylpyridine;

2-methyl-3-hydroxy-5-vinylpyrid-4-ylmethylthiosulfuric acid;

3-ethoxycarbonyloxy-4-ethoxycarbonylthiomethyl-2-methyl-5-vinylpyridine;and

bis[2-methyl-3-hydroxy-5-vinylpyrid-4-ylmethyl]disulfide or apharmaceutically acceptable salt thereof.

In the above descriptions R³ has been defined in part as --SO₃ H and--PO₃ H₂ to facilitate description. It is understood that moleculeswithin these descriptions actually exist as internal salts, havingstructures such as ##STR14## The Bunte salts as well as having utilityagainst rheumatoid arthritis, are valuable intermediates in thesynthesis of the disulfides. Thus, these Bunte salts form anotherembodiment of this invention. Certain of the other compounds describedabove can and do exist as isomers and cyclic internal condensationproducts, for example: ##STR15## and such cyclic isomers are consideredto be within the scope of the invention.

The pharmaceutically acceptable salts include those prepared frommineral and organic acids commonly employed in the pharmaceutical art,such as hydrochloric, hydrobromic, sulfuric, nitric, maleic, fumaric,tartaric, succinic acids, or the like, as well as alkali metal salts ofthe mercaptans, and the thiophosphoric acid and thiosulfuric acidanalogs described above, and divalent metallic complexes.

It is well known in the art that the mercapto group is subject toreaction with aldehydes and ketones to form hemimercaptals andhemimercaptoles. It is similarly known in the art, Field et al., J. Med.Chem. 12, 624-628 (1969) that many of these hemimercaptals andhemimercaptoles prepared from biologically active mercaptans serve as"latentiating" derivatives, or as chemical modifications of biologicallyactive compounds to form new compounds, which upon in vivo enzymatic orchemical transformation will liberate the parent compounds. Latentiationmay also provide means of favorably influencing absorption, transport,distribution, localization, metabolism, toxicity, and duration ofaction. as well as stability. Included with the group of aldehydes andketones suitable for this purpose are chloral, hexafluoro-acetone,acetone, benzaldehyde, pyruvate, and ketomalonate. Since latentiation ofmercapto groups by this means is known in the art, these latentiatingderivatives are considered to be within the spirit scope of the novelmethod of treatment and novel compounds of this invention.

Another means of latentiation is by addition of the thiols of thisinvention to α,β-unsaturated acids such as maleic acid and cinnamic acidas described by Srivistava et al., in J. Med. Chem., 16, 428-429 (1973).

Latentiation may also be achieved by substitution of the mercaptohydrogen with a 1-methyl-4-nitroimidazol-5-yl group as in azathioprineor a pivaloyloxymethyl group.

In spite of the extensive antiinflammatory research in the past twodecades, there is still an obvious need for an effective and welltolerated agent for the treatment of rheumatoid arthritis. Conventionalnonsteroidal antiinflammatory-analgesic-antipyretic agents, such asaspirin and many experimental new drugs under clinical evaluation, aremostly effective in providing symptomatic relief of the acute syndromeonly. As a consequence, the anti-rheumatic actions of two old remedies,gold and D-penicillamine, in spite of their potential side-effects, havereceived renewed interest in the past few years. The clinical efficacyof both drugs was reconfirmed by well-controlled multi-center clinicalstudies. Several rheumatologists have expressed the opinion that asuperior D-penicillamine-like compound would be a valuable contributionto medicine in this important field. It is, therefore, an importantdiscovery that the novel mercaptoalkyl pyridines of this invention havean important degree of anti-rheumatoid arthritis activity.

For this purpose the compounds of the invention may be administeredorally, topically, parenterally, by inhalation spray or rectally indosage unit formulations containing conventional non-toxicpharmaceutically acceptable carriers, adjuvants and vehicles. The termparenteral as used herein includes subcutaneous injections, intravenous,intramuscular, intrasternal, intraarticular, injection or infusiontechniques. In addition to the treatment of warm-blooded animals such asmice, rats, horses, dogs, cats, etc., the compounds of the invention areeffective in the treatment of humans.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide a pharmaceutically elegant andpalatable preparation. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, maize starch, or alginic acid;binding agents, for example starch, gelatine or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed.

Formulations for oral use may also be presented as hard gelatinecapsules wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatine capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin, orolive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyoxyethylene sorbitan monooleate.The said aqueous suspensions may also contain one or more preservatives,for example ethyl, or n-propyl, p-hydroxy benzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspension may be formulated by suspending the active ingredient ina vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of anantioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oils, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soya bean lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan mono-oleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan mono-oleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, sorbitol or sucrose. Such formulations may also contain ademulcent, a preservative and flavoring and coloring agents. Thepharmaceutical compositions may be in the form of a sterile injectablepreparation, for example as a sterile injectable aqueous or oleagenoussuspension. This suspension may be formulated according to the known artusing those suitable dispersing or wetting agents and suspending agentswhich have been mentioned above. The sterile injectable preparation mayalso be a sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butane diol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the antiinflammatory agents are employed.

Dosage levels of the order to 0.5 mg. to 140 mg. per kilogram of bodyweight per day are useful in the treatment of the above-indicatedconditions (25 mg. to 7 gms. per patient per day). For example,inflammation is effectively treated and anti-pyretic and analgesicactivity manifested by the administration of about .1 to 50 mg. of thecompound per kilogram of body weight per day (5 mg. to 3.5 gms. perpatient per day). Advantageously, from about 1 mg. to about 15 mg. perkilogram of body weight per daily dosage produces highly effectiveresults (50 mg. to 1 gm. per patient per day).

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration of humans may containfrom 5 mg. to 5 gm. of active agent compounded with an appropriate andconvenient amount of carrier material which may vary from about 5 toabout 95 percent of the total composition. Dosage unit forms willgenerally contain between from about 25 mg. to about 500 mg. of activeingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination and the severity ofthe particular disease undergoing therapy.

The novel compounds of this invention are generally prepared from knownpyridine derivatives.

Where the final product has a free α-mercaptoalkyl group in 2, 4, or 6position and is adjacent an hydroxyl substituent such as in2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine, it is readilyformed by dissolving the corresponding α-hydroxyalkyl compound in alower alkanol, preferably ethanol, containing an alkali metal hydroxide,such as sodium hydroxide or potassium hydroxide, treating the solutionwith carbon disulfide and heating for 2-8 hours at a temperature from50° C. to reflux, followed by acidification of the cooled mixture.Isolation is accomplished by standard techniques such as concentrationto dryness and extraction with a solvent.

An alternative procedure for producing a free α-mercaptoalkyl groupirrespective of its location on the pyridine nucleus is the removal ofprotective groups from a preformed thio compound. For example, S-acylcompounds, such as the S-benzoyl, are converted to the free mercapto byart recognized hydrolytic procedures, for example by saponification withdilute alkali at room temperature to about 75° C.

The mercaptoalkyl group in any position may also be prepared by firstconverting the corresponding hydroxyalkyl group to the chloromethyl orbromomethyl by heating at 50° C. to reflux temperature for 1-4 hourswith thionyl chloride or with concentrated hydrobromic acidrespectively. The resulting halo methyl compound is then treated in oneof two alternate procedures.

a. The halomethyl compound in aqueous solution is treated with a loweralkyl alkali metal xanthogenate, such as ethyl potassium xanthogenate at5-10° C. for 1-4 days, and the xanthate product is extracted out with asolvent such as ether and reduced with lithium aluminum hydride orsodium borohydride. Alternatively, the xanthate can be converted tomercapto by heating at 50° C. to reflux with aqueous alcoholic alkalisuch as sodium or potassium hydroxide. B. The halomethyl compound isheated in a lower alkanol such as methanol, with thiourea at 50° C. toreflux for 1-4 hours. The isothioureide is then heated at 50° C. toreflux in water or a lower alkanol such as ethanol containing an alkalimetal hydroxide such as sodium or potassium hydroxide preferably in aninert atmosphere such as nitrogen. Alternatively, the thioureide may bereduced with lithium aluminum hydride or lithium borohydride aspreviously described.

The Bunte salts of the mercaptoalkyl compounds of this invention areprepared from the corresponding chloro- or bromomethyl compounds andsodium thiosulfate in aqueous alcohol by warming the mixture at 50° toreflux for a few minutes to about 2 hours.

These Bunte salts, as well as being useful in the novel method oftreatment, find utility as an intermediate to the disulfides, bothsymmetrical and unsymmetrical and also to the free mercaptomethylcompounds.

The mercaptomethyl compounds are obtained from the Bunte salts byreduction with lithium aluminum hydride or sodium borohydride at -10° to10° C. in an inert organic solvent, such as tetrahydrofuran or mixturesof tetrahydrofuran and ether.

Disulfides are obtained from the Bunte salts by mixing at 20-100° C.approximately molar equivalents of a Bunte salt and a sulfhydrylcompound such as penicillamine, an alkylmercaptan, etc., or amercaptomethyl pyridine of this invention such as2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine with an aqueousalkali metal hydroxide such as sodium or potassium hydroxide.

Alternatively, a Bunte salt, such as that of2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine, is converted to thesymmetrical disulfide such asbis[2-methyl-3-hydroxy-5-vinylpyridyl-4-methyl]disulfide by variousprocedures: (a) by treating it with aqueous alkali or dilute mineralacid at 20°-100° C.; (b) by treating it with Na₂ S₂ in an aqueousalkanol at 20°-100° C. for 3-24 hours; (c) by treating it with Na₂ S inan aqueous alkanol at 20°-100° C. for a few minutes to about 4 hours; or(d) by treating it with iodine at ambient temperature in an aqueousalkanol for 8-24 hours.

Another procedure for obtaining symmetrical disulfides such asbis[2-methyl-3-hydroxy-5-vinylpyridyl-4-methyl]disulfide is by treatingan hydroxyalkyl compound such as2-methyl-3-hydroxy-4-hydroxymethylpyridine with phosphorus pentasulfidein a solvent such as pyridine at 50° to reflux temperature for 2-10hours followed by acidification and further heating for 1-4 hours.

A further procedure for obtaining symmetrical disulfides such asbis[2-methyl-3-hydroxy-5-vinylpyridyl-4-methyl]disulfide is by treatingan isothiuronium salt such as 2-methyl-3-hydroxy-5-vinylpyridyl-4-methylisothiuronium salt at 10° to room temperature with dilute aqueouscaustic such as 5-15% (w/v) sodium hydroxide and aqueous hydrogenperoxide for a few minutes to 2 hours.

Similarly, an isothiuronium salt can be converted to a disulfide bysubstituting sodium tetrathionate in the above reaction, followed byacidification to about pH 5-7.

The alkyl xanthogenates of this invention such as2-methyl-3-hydroxy-5-vinylpyridyl-4-methyl ethyl xanthogenate are alsoconverted to disulfides by treatment with ammonium hydroxide and slowaddition of hydrogen peroxide at 0°-15° C. in aqueous alkanolic solutionfor 1-5 hours.

An additional procedure for preparing the symmetrical disulfides of thisinvention such asbis[2-methyl-3-hydroxy-5-vinylpyridyl-4-methyl]disulfide is by treatinga compound of formula: ##STR16## where Q is a facile leaving group suchas chloro, bromo, iodo, methanesulfonyloxy, benzenesulfonyloxy,toluenesulfonyloxy, or the like, with sodium sulfide (Na₂ S₂). Thereaction is conducted in aqueous alkanol at about room temperaturealthough temperature is not critical for 2-24 hours.

The disulfide dimers may also be prepared from the corresponding monomerxanthate by treating it for 12 hours to 4 days at room temperature withconcentrated ammonium hydroxide.

Another method of preparing the disulfide dimers involves oxidation ofthe corresponding monomer by bubbling air through a solution of themonomer in dilute ammonium hydroxide at 20°-50° C. for 15-30 hours, orin an organic solvent at 20°-50° for periods of 1-4 days.

Alternatively, the monomer may be oxidized with a per-acid such asm-chloroperbenzoic acid, peracetic acid, perphthalic acid, sodiumhypochlorite, iodine, or hydrogen peroxide in aqueous solution at about0°-15° C.

As well as being a final product, a disulfide is frequently employed asa convenient means of protecting the mercapto group while manipulatingother functional groups on the molecule. In this event, the monomer issubsequently obtained by reduction. Useful reducing systems are lithiumaluminum hydride in ether at room temperature for 1-20 hours; zinc inhydrochloric acid; zinc in acetic acid; or tin in hydrochloric acid.

Another type of derivative found useful both as a final product and asparticularly useful protective groups because they tie up both anhydroxyl group and a vicinal hydroxymethyl or mercaptomethyl, are cyclicketals and acetals. They are prepared by treating, for example, a3-hydroxy-4-mercaptomethyl compound with a carbonyl compound such asacetone or benzaldehyde saturated with hydrogen chloride at -5° to +5°C. for 2-6 hours.

A typical derivative is: ##STR17##

Where the desired product is in the form of its N-oxide, the oxygen mustbe introduced before the mercapto group, as the latter is subject tooxidation. The N-oxides are usually prepared by treating a pyridine freebase with a peracid such as m-chloroperbenzoic acid at room temperaturein an inert solvent such as chloroform, or methylene chloride for aperiod of 16-48 hours.

Another type of cyclic compound are those of structure: ##STR18## whereR⁵ and R.sub.α⁵ taken together, represent ═O and ═S. These cycliccompounds are prepared simply by adding phosgene or thiophosgene in aninert solvent such pyridine benzene, chloroform, tetrahydrofuran, or thelike, to a solution of the free mercapto compound in a similar solventat -5° to +10° C. and then aging at room temperature overnight.

Certain other useful end products are considered as biologicalequivalents of the mercaptomethyl compounds.

One such is the thiophosphoric acid prepared by treating a chloroalkylcompound with trisodium phosphorothioate in aqueous solution at about 0°C. and aging the mixture for 10-20 hours at 0°-10° C. followed byacidification.

Another type of useful end product is the S-ester or carbamoyl. Theseare generally formed by treating the mercaptoalkyl compound with anacylating compound such as a carboxylic anhydride or carboxylic chlorideor a carbamoyl chloride in an inert organic solvent such astetrahydrofuran with or without the presence of an acid acceptor such aspyridine or triethylamine or the pyridine nitrogen of the substrateitself. Where the substrate carries a free hydroxyl group as well as themercaptoalkyl group, it too may become acylated. However, by control ofthe amount of acylating agent, either the S-acyl or the O,S-diacylcompound can be obtained. The reaction is conducted at room temperatureto reflux temperature for 1 hour to 2 days.

Related acylating procedures conducted generally as described above forthe normal acylation involves the use of reagents having dual acylgroups such as isophthaloyl chloride, N,N'-dichlorcarbonylpiperazine,phosgene, oxalyl chloride, glutaroyl chloride, succinoyl chloride, orpentane-dicarbonyl chloride, which result in symmetricaldicarbothioates.

Phosgene is also a useful reagent for preparing S-carbamates. By usingan excess of phosgene and adding a mercaptoalkylpyridine dropwisefollowed by evaporation of excess phosgene and treatment with an aminocompound such as ammonia or an amino acid ester at room temperature for3-24 hours.

The compounds, where R³ is ##STR19## are prepared by treating a chloro-or bromoalkylpyridine with disodium trithiocarbonate in a lower alkanolat 10°-50° C. for 1-6 hours.

Similarly prepared are compounds wherein R³ is ##STR20## (alkali metal).In this case the solvent is preferably an aqueous alkanol, and an excessof the alkali metal trithiocarbonate is employed. After adjusting the pHto 6.2-6.5 with dilute acid, the product precipitates.

Another type of useful end-product are the sulfenamides of structure:##STR21## These are prepared by treating the mercaptoalkyl compoundswith thiocyanogen in an inert solvent such as ether. The resultingprecipitate is then treated with di(C₁₋₄ alkyl) amine for 1/2 to 3hours.

Related to the previously described disulfides is the disulfiderepresented by the partial structural formula: ##STR22## This compoundis prepared by treating a mercaptoalkyl compound witho-carboxyphenyl-o-carboxybenzenthiolsulfonate in a lower alkanol for4-24 hours at 10°-50° C.

An alternative procedure for the preparation of S-acyl compounds is bytreatment of a corresponding halomethyl compound with an alkali metalthioacyl compound such as potassium thiobenzoate, in an inert solventsuch as an aqueous alkanol at room temperature to about 100° C. for 1/2to 3 hours.

Another novel unsymmetrical disulfide is that prepared from themercaptoalkyl compounds of this invention and thiamine-S-monooxideprepared by suspending the latter in water and adding the former slowlywith stirring. After 1/2 or 3 hours at room temperature to about 50° C.,the mixture is filtered, and the product is extracted from the filtrate.

The compounds, wherein R³ is --CH₂ CO₂ Et and --CH₂ CH(NH)CO₂ H, areprepared by treating a bromo- or chloromethylpyridine with ethylmercaptoacetate or cysteine respectively in a lower alkanol and in thepresence of a strong base such as a sodium alkoxide in sufficientquantity both to react with any acidic functional groups such as anuclear hydroxyl on the pyridine ring or the carboxyl group of cysteineand to neutralize the HBr or HCl produced in the condensation reaction.

As well as the disulfides described above, polysulfides, particularlythe tri- and tetra- sulfides are a further embodiment of this invention.They are prepared by forming an alkali metal salt of the sulfhydrylgroup by treating one of the mercaptomethyl pyridines of this inventionin an aprotic solvent such as dimethyl formamide, dimethyl sulfoxide, orthe like, with an alkali metal hydride such as sodium hydride or analkali organic compound such as n-butyl lithium or sodium phenyl, at-10° C. to +10° C., followed by treatment of the alkali metal sulfidewith sulfur dichloride (SCl₂) or sulfur monochloride (S₂ Cl₂) for 5-24hours. The reaction is quenched by addition of water and the trisulfideor tetrasulfide respectively is isolated by extraction.

If the mercaptoalkyl compound in the above reaction carries a freehydroxyl or other functional group that could participate in reactionwith the reagents, it is advisable to protect it with a standardblocking group such as benzyl.

The novel compounds of this invention also carry an alkenyl or alkynylsubstituent. The alkenyl is generally prepared from the correspondingformylpyridine by means of a standard Wittig reagent, for example,triphenylmethylphosphonium bromide in the presence of a strong base suchas sodium hydride in a solvent such as dimethyl sulfoxide. The reactionis best conducted in the cold, below about 25° C. followed by aging atroom temperature for prolonged periods such as 1-3 days or by heating attemperatures of 40°-90° C. for 1 to 7 hours.

Where the vinyl substituent carries plural halo substituents, reactionsrelated to the Wittig reaction are employed which involve preparation ofthe Wittig reagent in situ. For example, the dichlorovinyl andchlorofluorovinyl group are introduced by treating a pyridine aldehydewith a mixture of triphenylphosphine, potassium t-butoxide andchloroform or dichlorofluoromethane at 40°-50° C. for 2-7 hours. Thedifluorovinyl analog is prepared by treating the pyridinealdehyde withtriphenylphosphine and sodium chlorodifluoroacetate in glyme or diglymeat 60°-100° C. for 16-48 hours.

Alternatively, the alkenyl group may be prepared from a formylpyridineby first subjecting it to a Grignard reaction under standard conditionsto form an α-hydroxyalkylpyridine followed by thermal dehydration of the≢-hydroxy compound by refluxing in a high boiling solvent such asdiethyleneglycol dimethyl ether (diglyme).

The alkynyl analogs are readily prepared from the corresponding alkenylcompounds by addition of bromine across the double bond by simplyaddding bromine dropwise to the alkene in an inert solvent such aschloroform preferably at about 0°-20° C., followed by doubledehydrobromination. The dehydrobromination occurs on heating the dibromocompound in alcoholic alkali such as alcoholic potassium hydroxide.

Various other synthetic procedures are employed to prepare pyridinederivatives with the desired substitution to serve as intermediates forfinal conversion to the mercaptoalkylpyridines of this invention. All ofthese procedures are well known in the art and available to skilledpractitioners. Details of these procedures are provided in the examplesthat follow for the preparation of specific novel compounds from knownstarting materials.

EXAMPLE 1 2-Methyl-3-Hydroxy-4 Mercaptomethyl-5-VinylpyridineHydrochloride Step A: Preparation of 3,4α-di-O-isopropylidene derivativeof 2-methyl-3-hydroxy-4-hydroxymethyl-5-vinylpyridine

67 Ml. of n-butyl lithium (1.9 M in n-hexane) was run into a stirredsuspension of triphenylmethylphosphonium bromide (42.7 g., 0.12 M) atroom temperature in tetrahydrofuran (300 ml.) under nitrogen. To thisstirred solution a solution of the 3,4α-di-O-isopropylidene derivativeof 2-methyl-3-hydroxy-4-hydroxylmethyl-5-formylpyridine (24.7 gm. 0.119M) in tetrahydrofuran (300 ml.) was added dropwise over 1 hour. Thereaction was aged 1 hour at room temperature and the refluxed for 4hours.

The solution was evaporated to dryness first under house pump vacuumthen high vacuum at 30°-50° C. The red-oily product was triturated with400 ml. ether. Solid triphenylphosphine oxide was filtered off (17.0gm.) and the ether filtrate was extracted with 2 × 200 ml. saturatedsodium bisulfite solution and evaporated to dryness to give areddish-yellow oil. The product was used as in the next step.

Step B: Preparation of2-methyl-3-hydroxy-4-hydroxymethyl-5-vinylpyridine hydrochloride

A solution of the red oil obtained above (25 gm. 0.122 M) was stirred in2.5 N hydrochloric acid (500 ml.) and acetone (500 ml.) at reflux undernitrogen for 1.5 hours. The acetone was distilled off to a temperatureof 90° and the cooled solution was extracted with ethyl acetate (3 × 400ml.). The aqueous layer was poured into excess saturated sodiumbicarbonate solution (700 ml.).

The aqueous layer was extracted with ethyl acetate (1 × 400 ml.). Theorganic solution was dried (MgSO₄), filtered and evaporated to give anoff-white solid recrystallizable from ethyl acetate, m.p. 164°-166°, 9.4gm.

Step C: Preparation of2-methyl-3-hydroxy-4-mercaptiomethyl-5-vinylpyridine hydrochloride

To a 1 liter 3-necked flask equipped with nitrogen inlet tube athermometer and additional funnel on top of a condenser was added 530ml. of 90% ethanol and 53.4 gm. of NaOH. After solution was complete, 50gm. of produce from Step B was added. To the resulting solution (underN₂) was added 30 ml. of SC₂ dropwise over a period of about 1/2 hourwith stirring at 10°-15°. The resulting mixture was then stirred for 1/2hour at 20°, then cooled to about 15° C. and an additional 20 ml. of CS₂was added dropwise and refluxed for 4 hours. The mixture was then cooledto about 10° C. and concentrated HCl was added until the pH remained at2. (About 80 ml. required). The mixture was kept in an ice bathovernight, and concentrated under reduced pressure (bath temperature20°) to remove the ethanol. The resulting material was added (N₂ atmos)to a cold stirred suspension of 120 gm. of NaHCO₃ in 1 liter of water.The organic material was extracted with 3 × 300 ml. of ethyl acetate(air excluded as much as possible). The combined extracts were dried(MgSO₄), filtered and concentrated under reduced pressure. The residuewas purified by chromatography using about 1 kg. of SiO₂ (Baker) andethyl acetate as the eluant. The appropriate fractions (as determine bytlc-EtOAc dev) were combined and concentrated to an appropriate volumegiving the white crystalline free base. lst crop. m.p. 115°-117° (33gm). Crop 2, m.p. 114°-116° (6 gm.).

Anal. C₉ H₁₁ NOS. Calcd: C, 59.66; H, 6.12; N, 7.73; D, 17.7. Found: C,59.64; H, 6.35; N, 7.26; S, 17.30.

It was converted to the hydrochloride by the following procedure:

The free base (39 gm.) was dissolved in 500 ml. of dry THF and, withstirring, dry HCl was admitted keeping the temperature below 25° until aslight excess was present. The resulting white precipitate wascollected, washed with tetrahydrofuran and dried under vac. m.p.149°-152°, wt 45 g.

Anal. C₉ H₁₂ ClNOS, m.w. 217.7 Calcd: C, 49.65; H, 5.56; N, 6.44; S,14.73. Found: C, 49.87; H, 5.82; N, 6.44; S, 15.10.

Employing the procedure substantially as described in Example 1, butsubstituting for the triphenylmethylphosphonium bromide used in Step Athereof, an equivalent amount of triphenylethylphosphonium bromide,triphynelbenzylphosphonium bromide and triphenylchloromethylphosphoniumbromide, there are prepared in sequence, respectively,

Step A:

3,4α-di-O-isopropylidene derivative of2-methyl-3-hydroxy-4-hydroxymethyl-5-(1-propenyl)pyridine (oil, 35%yield);

3,4α-di-O-isopropylidene derivative of2-methyl-3-hydroxy-4-hydroxymethyl-5-styrylpyridine; and

3,4α-di-O-isopropylidene derivative of2-methyl-3-hydroxy-4-hydroxymethyl-5-(2-chlorovinyl) pyridine.

Step B:

2-methyl-3-hydroxy-4-hydroxymethyl-5-(1-propenyl)pyridine hydrochloride(100% yield);

2-methyl-3-hydroxy-4-hydroxymethyl-5-styrylpyridine hydrochloride; and

2-methyl-3-hydroxy-4-hydroxymethyl-5-(2-chlorovinyl)pyridinehydrochloride.

Step C:

2-methyl-3-hydroxy-4-mercaptomethyl-5-(1-propenyl)pyridine hydrochlorine(60% yield, m.p. 175°-178° C);

2-methyl-3-hydroxy-4-mercaptomethyl-5-styrylpyridine hydrochloride (m.p.190°-195° C.); and

2-methyl-3-hydroxy-4-mercaptomethyl-5-(2-chlorovinyl)pyridinehydrochloride.

EXAMPLE 2 2-Methyl-3-Hydroxy-4-Mercaptomethylpyridine-5-Acrylic AcidHydrochloride

A mixture of 1.23 g. of2-methyl-3-hydroxy-4-hydroxymethylpyridine-5-acrylic acid, 1 g. ofsodium metal, 5 ml. of carbon disulfide, and 75 ml. of absolute ethanolwas refluxed for 26 hours. Concentrated hydrochloric acid (3 ml.) wasadded and the mixture was evaporated to dryness. The residue wasextracted with 125 ml. of boiling ethanol and filtered hot. Evaporationof the extract gave a syrup which was crystallized from chloroform-etherto give 2-methyl-3-hydroxy-4-mercaptomethylpyridine-5-acrylic acidhydrochloride, m.p. 227°-228° C.

EXAMPLE 3 2-Methyl-3-Hydroxy-4-Vinyl-5-Benzoylthimethylpyridine Step A:Preparation of 3,4α-di-O-isopropylidene derivative of2-methyl-3-hydroxy-4-hydroxymethyl-5-benzoylthiomethylpyridine

To a stirred solution of 80 g. of the 3,4α-di-O-isopropylidenederivative of 2-methyl-3-hydroxy-4-hydroxymethyl-5-chloromethylpyridinein 1 liter of ethanol under nitrogen there was added 96 g. of potassiumthiobenzoate in 200 ml. of water over 30 minutes. After 1 hour, theethanol was evaporated at 40° C. and the aqueous solution was extractedwith 4 × 300 ml. of ethyl acetate. The extract was washed with 1 × 75ml. of water, dried over magnisium sulfate and concentrated to drynessto give 116 g. of 3,4α-di-O-isopropylidene derivative of2-methyl-3-hydroxy-4-hydroxymethyl-5-benzoylthiomethylpyridine, m.p.74°-77° C.

Step B: Preparation of2-methyl-3-hydroxy-4-hydroxymethyl-5-benzoylthiomethylpyridine

The product from Step A was dissolved in 1 liter of ethanol and wastreated with 1 liter of 2.5 N hydrochloric acid. The mixture was heatedon a steam bath for 30 minutes. The ethanol was evaporated at 60° C. andthe aqueous solution was poured into excess sodium bicarbonate solution.The precipitate was collected and dried to give 48 g. of2methyl-3-hydroxy-4-hydroxymethyl-5 -benzoylthiomethylpyridine, m.p.174°-177° C.

Step C: Preparation of2-methyl-3-hydroxy-4-formyl-5-benzoylthiomethylpyridine

A solution of the 10 g. of the product from Step B in 300 ml. of hotchloroform was treated with 100 g. of maganese dioxide. After 1/2 hourof stirring, the mixture was filtered and the filtrate was evaporated todryness to give 9.2 g. of2-methyl-3-hydroxy-4-formyl-5-benzoylthiomethylpyrididne, m.p. 127°-130°C.

Step D: Preparation of2-methyl-3-acetoxy-4-formyl-5-benzoylthiomethylpyridine

A mixture of 11 g. of product from Step C, 4.62 g. of acetic anhydride,4.62 g. of triethylamine, and 30 ml. of dry tetrahydrofuran was aged atroom temperature for 1.5 hours and evaporated at 20° to a small volume.The residue was diluted with ethyl acetate, washed with water, driedover magnesium sulfate, and evaporated to dryness to give 12.3 g. of2-methyl-3-acetoxy-4-formyl-5-benzoylthiomethylpyridine, m.p. 128°-130°C. (dec.).

Step E: Preparation of2-methyl-3-acetoxy-4-(1-hydroxyethyl)-5-benzoylthiomethylpyridine

To a stirred suspension of the aldehyde (6.58 g.) in tetrahydrofuran(200 ml.), methyl magnesium bromide (0.02 mole; 6 ml. of 3.6 M intetrahydrofuran) (6.6 ml.) was added dropwise and the mixture wasstirred overnight at room temperature. The reaction mixture was pouredinto 500 ml. of an ice-water solution of ammonium chloride (100 gm.),stirred for a few minutes and extracted well with ether (4 × 300 ml.).The combined extracts were washed with water, dried over magnesiumsulfate, filtered and evaporated to give an oil which was used directlyin the next step.

Step F: Preparation of2-methyl-3-hydroxy-4-vinyl-5-benzoylthiomethylpyridine

The product from Step E (2 gm.) was added to diglyme and refluxed 3hours. The mixture was evaporated to dryness to give2-methyl-3-hydroxy-4-vinyl-5-benzoylthiomethylpyridine. This materialwas purified by chromatography on 800 gm. of silica gel by elution with10% methanol in chloroform (v/v).

EXAMPLE 4 2-Methyl-3-Hydroxy-4-Vinyl-5-Mercaptomethylpyridine

A mixture of 1 g. of2-methyl-3-hydroxy-4-vinyl-5-benzoylthiomethylpyridine, 10 ml. oftetrahydrofuran and 10 ml. of 2.5 N aqueous sodium hydroxide was aged atroom temperature overnight. The solution was acidified to about pH 6with hydrochloric acid and then adjusted to pH 7.5 with solid sodiumbicarbonate. The mixture was extracted with 3 × 100 ml. of ethylacetate:isopropanol (9:1 v/v). The extract was dried over magnesiumsulfate and concentrated to an oil which crystallized on triturationwith ether to give 175 mg. of2-methyl-3-hydroxy-4-vinyl-5-mercaptomethylpyridine, m.p. 130°-140° C.

EXAMPLE 5 2-Methyl-3-Hydroxy-4-Acetylthiomethyl-5-Vinylpyridine

A mixture of 2.54 g. of2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine hydrochloride, 120ml. of anhydrous tetrahydrofuran, 3.82 ml. of triethylamine, and 1.32ml. of acetic anhydride was aged overnight at room temperature. Afterevaporating to dryness, the residue was dissolved in ethyl acetate,extracted with aqueous sodium bicarbonate solution, dried over magnesiumsulfate, and evaporated to dryness. After trituration with ether, theresidue crystallized to give 0.8 g. of2-methyl-3-hydroxy-4-acetylthiomethyl-5-vinylpyridine, m.p. 130°-132° C.

EXAMPLE 6 2-Methyl-3-Acetoxy-4-Acetylthiomethyl-5-Vinylpyridine

A mixture of 680 mg. of acetic anhydride and 10 ml. of tetrahydrofuranwas added slowly to 653 mg. of2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine in 20 ml. oftetrahydrofuran at 10° C. After stirring for one hour at roomtemperature, the mixture was evaporated to dryness. The residue wastriturated with a mixture of 20 ml. of ethyl acetate and 20 ml. ofwater. The ethyl acetate was separated, dried over magnesium sulfate,and evaporated to dryness. The residue was recrystallized fromcyclohexane to give2-methyl-3-acetoxy-4-acetylthiomethyl-5-vinylpyridine, m.p. 72°-73° C.The same product is obtained by starting with the S-acetate product ofExample 5.

EXAMPLE 7 3-O-4α-S-Benzylidene Derivative of2-Methyl-3-Hydroxy-4-Mercaptomethyl-5-Vinylpyridine

2-Methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine (1 g.) was dissolvedin tetrahydrofuran and stirred at 0° C. with 900 mg. of benzaldehydewhile gaseous hydrogen chloride was introduced over a 2 hour period.After aging overnight at room temperature, the mixture was evaporated todryness. The residue was taken up in water and poured onto excess solidsodium bicarbonate and extracted with ethyl acetate. The extract wasdried and evaporated to dryness, and the residue was chromatographed onsilica gel by elution with tetrahydrofuran to give 220 mg. of3-O-4α-S-benzylidene derivative of2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine (oil).

Similarly prepared were the 3-O-4α-S-(2,4-difluorobenzylidine),3,O-4α-S-(2,4-dimethylbenzylidine), and 3-O-4α-S-isopropylidinederivatives of 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine.

EXAMPLE 8 Ethylcarbonates of2-Methyl-3-Hydroxy-4-Mercaptomethyl-5-Vinylpyridine

A solution of 1.1 g. of2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine in 50 ml. of drytetrahydrofuran and 10 ml. of dry pyridine was stirred at roomtemperature and ethylchloroformate (20% excess) in 10 ml. oftetrahydrofuran was added over 10 minutes. After 1 hour the solution wasevaporated to about 5 ml. and diluted with 100 ml. of ethyl acetate andextracted with water. The organic layer was dried and concentrated todryness and chromatographed on silica gel by elution with 1:1 (v/v)ether-hexane to give, after conversion to the hydrochloride salt:

2-methyl-3-ethoxycarbonyloxy-4-ethoxycarbonylthiomethyl-5-vinylpyridine.HCl,m.p. 142°-145° C.; and

2-methyl-3-hydroxy-4-ethoxycarbonylthiomethyl-5-vinylpyridine.HCl.

Following the procedure of Example 8 but substituting for theethylchloroformate used therein, equivalent amounts of adamantanoylchloride, cyclopropylcarbonyl chloride, 2-acetoxysalicyloyl chloride,benzoyl chloride, 2-hydroxy-4-(2,3-difluorophenyl)benzoyl chloride,3-chloro-4-allyloxyphenylacetyl chloride,α-methyl-4-isobutylphenylacetyl chloride, α-methyl-3-phenoxyphenylacetylchloride, α-methyl-3-benzoylphenylacetyl chloride,α-methyl-6-methoxynaphth-2-ylacetyl chloride,α-methyl-3-fluoro-4-phenylphenylacetyl chloride,4-(3-chloro-4-cyclohexylphenyl)-4-ketobutyryl chloride,2-(3-trifluoromethylanilino)benzoyl chloride,2-(2,3-dimethylanilino)benzoyl chloride,2-(2,6-dichloro-3-methylanilino)benzoyl chloride,2-(3-trifluoromethylanilino)nicotinoyl chloride,2-(2-methyl-3-chloroanilino)nicotinoyl chloride, there are producedrespectively the S-mono and O,S-di- adamantanoyl, cyclopropanoyl,2-acetoxybenzoyl, benzoyl, 2-hydroxy-4-(2,4-difluorophenyl)benzoyl,3-chloro-4-allyloxyphenylacetyl, α-methyl-4-isobutylphenylacetyl,α-methyl-3-phenoxyphenylacetyl, α-methyl-3-benzoylphenylacetyl,α-methyl-6-methoxynaphth-2-ylacetyl,α-methyl-3-fluoro-4-phenylphenylacetyl, 4(3-chloro-4-cyclohexylphenyl)-4-ketobutyryl,2-(3-trifluoromethylanilino)benzoyl, 2-(2,3-dimethylanilino)benzoyl,2-(2,6-dichloro-3-methylanilino)benzoyl,2-(3-trifluoromethylanilino)-nicotinoyl,2-(2-methyl-3-chloroanilino)nicotinoyl derivatives of2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine.

Following the procedure of Example 8 but substituting for the2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine used therein anequivalent amount of2-methyl-3-hydroxy-4-mercaptomethyl-5-ethynylpyridine (Example 9) thereare produced:

2-methyl-3-ethoxycarbonyloxy-4-ethoxycarbonylthiomethyl-5-ethynylpyridine;

2-methyl-3-hydroxy-4-ethoxycarbonylthiomethyl-5-ethynylpyridine;

2-methyl-3-adamantanoyloxy-4-adamantanoylthiomethyl-5-ethynylpyridine;

2-methyl-3-hydroxy-4-adamantanoylthiomethyl-5-ethynylpyridine;

2-methyl-3-cyclopropanoyloxy-4-cyclopropanoylthiomethyl-5-ethynylpyridine;

2-methyl-3-hydroxy-4-cyclopropanoylthiomethyl-5-ethynylpyridine;

2-methyl-3-(2-acetoxybenzoyloxy)-4-acetoxybenzoylthiomethyl)-5-ethynylpyridine;

2-methyl-3-hydroxy-4-(2-acetoxybenzoylthiomethyl)-5-ethynylpyridine.

EXAMPLE 9 2-Methyl-3-Hydroxy-4-Mercaptomethyl-5-EthynylpyridineHydrochloride Step A: Preparation of2-methyl-3-hydroxy-4-hydroxymethyl-5-(1,2-dibromoethyl)pyridine

Bromine (320 mg.) was added over 10 minutes to a stirred suspension of320 mg. of 2-methyl-3-hydroxy-4-hydroxymethyl-5-vinylpyridine inchloroform at 10° C. After stirring 10 minutes, the mixture wasevaporated to an oil.

Step B: Preparation of2-methyl-3-hydroxy-4-hydroxymethyl-5-ethynylpyridine

The oily product from Step A was refluxed in 15 ml. of 10% (w/v)ethanolic potassium hydroxide under nitrogen for 10 minutes. Aftercooling the solvent was evaporated. The residue was extracted with 2 ×20 ml. of hot isopropanol which was then filtered and evaporated to givesolid 2-methyl-3-hydroxy-4-hydroxymethyl-5-ethynylpyridine, m.p.170°-171° C.

Step C: Preparation of2-methyl-3-hydroxy-4-mercaptomethyl-5-ethynylpyridine hydrochloride

The product from Step B (3.26 g.) was treated with 1.6 g. of sodiumhydroxide and 3 ml. of carbon disulfide according to the proceduredescribed in Example 1, Step C, to give2-methyl-3-hydroxy-4-mercaptomethyl-5-ethynylpyridine hydrochloride,m.p. 114°-126° C. (dec.).

EXAMPLE 10 2-Methyl-3-Hydroxy-4-(1-mercaptoethyl)-5-Vinylpyridine StepA: Preparation of 2-methyl-3-hydroxy-4-formyl-5-vinylpyridine

A solution of 10 g. of2-methyl-3-hydroxy-4-hydroxymethyl-5-vinylpyridine in 300 ml. of hotchloroform was treated with 100 g. of manganese dioxide. After 1/2 hourof stirring, the mixture was filtered and the filtrate was evaporated todryness to give 2-methyl-3-hydroxy-4-formyl-5-vinylpyridine.

Step B: Preparation of2-methyl-3-hydroxy-4-(1-hydroxyethyl)-5-vinylpyridine

To a stirred suspension of the aldehyde (0.2 mole) in tetrahydrofuran(200 ml.), methyl magnesium chloride (0.44 mole; 3.35 M intetrahydrofuran) (13.2 ml.) was added dropwise and the mixture wasstirred overnight at room temperature. The reaction mixture was pouredinto 500 ml. of an ice-water solution of ammonium chloride (100 gm.),stirred for a few minutes and extracted well with ether (4 × 300 ml.).The combined extracts were washed with water, dried over magnesiumsulfate, filtered and evaporated to give an oil which was used directlyin the next step.

Step C: Preparation of2-methyl-3-hydroxy-4-(1-mercaptoethyl)-5-vinylpyridine

Prepared by the procedure of Example 1, Step C, to yield2-methyl-3-hydroxy-4-(1-mercaptoethyl)-5-vinylpyridine.

EXAMPLE 11 2-Methyl-3-Hydroxy-4-(2-mercaptobut-2-yl)-5-VinylpyridineStep A: Preparation of 2-methyl-3-hydroxy-4-acetyl-5-vinylpyridine

To 750 ml. of dry methylene chloride containing 47.5 ml. of dry pyridinewas added with stirring and cooling 29.6 g. of chromium trioxide. Themixture was aged 20 minutes at room temperature and then treated with asolution of 10.96 g. of the product from Example 10, Step B, in 250 ml.of dry methylene chloride over 15 minutes. After one hour at roomtemperature, the reaction mixture was filtered and the residue waswashed with 2 × 100 ml. of methylene chloride. The methylene chloridefiltrates were extracted with 3 × 500 ml. of 5% (w/w) aqueous sodiumhydroxide solution, dried over magnesium sulfate and evaporated todryness. The residue was crystallized from hexane to give2-methyl-3-hydroxy-4-acetyl-5-vinylpyridine.

Step B: Preparation of2-methyl-3-hydroxy-4-(2-hydroxybut-2-yl)-5-vinylpyridine

A solution of 3.93 g. of the product from Step A in 200 ml. oftetrahydrofuran was treated dropwise with 110% excess of ethyl magnesiumbromide in tetrahydrofuran. After aging 2 days at ambient temperaturethe reaction was quenched on ice-water (100 ml.) containing 10 g. ofammonium chloride. The aqueous layer was separated and extracted withether. The combined organic layers were dried over magnesium sulfate andevaporated to dryness to give2-methyl-3-hydroxy-4-(2-hydroxybut-2-yl)-5-vinylpyridine, which was useddirectly in the next step.

Step C: Preparation of2-methyl-3-hydroxy-4-(2-mercaptobut-2-yl)-5-vinylpyridine

Prepared by the procedure of Example 1, Step C, to yield2-methyl-3-hydroxy-4-(2-mercaptobut-2-yl)-5-vinylpyridine.

EXAMPLE 12 2-Vinyl-3-Hydroxy-4-Mercaptomethyl-5-HydroxymethylpyridineStep A: Preparation of ethyl α-formyl-α-formamidoacetate diethylacetal

A solution of ethyl α-formyl-α-formamido acetate (1 equivalent) in 200ml. anhydrous ethanol is saturated with dry hydrogen chloride at 0° C.The solution is allowed to reach room temperature and is aged for 16hours. The solution is then concentrated under reduced pressure to yieldthe desired acetal as an oil.

Step B: Preparation of 4-formyl-5-ethoxyoxazole diethyl acetal

A 2 liter flask is charged with 340 ml. anhydrous chloroform and 142 gm.phosphorus pentoxide. To this stirred mixture, a solution of 0.5 moleethyl α-formyl-α-formamidoacetate diethyl acetal in 200 ml. chloroformis added over 10 minutes. The reaction is then maintained under gentlereflux for 6 hours. To the cooled reaction mixture is added 750 ml. 20%potassium hydroxide solution with good agitation over 1.5 hours. Afteraddition is complete, aging is continued for 30-60 minutes at roomtemperature. The layers are separated, and the aqueous phase isextracted with fresh chloroform (2 × 200 ml.). The combined chloroformextracts are dried over anhydrous magnesium sulfate. After solventremoval, the residual oil is distilled at reduced pressure to afford thedesired oxazole.

Step C: Preparation of diethyl2-formyl-3-hydroxypyridine-4,5-dicarboxylate diethyl acetal

A mixture of 31 gm. (0.2 m) diethyl maleate and 0.1 m of oxazole fromStep A is charged to a flask and heated to 110°-115° C. for 4 hours. Themixture is cooled and 20 ml. of a 25% solution of dry hydrogen chloridein absolute ethanol is added. Then 300 ml. ether is introduced and aftercooling overnight, the crystalline hydrochloride is isolated. Thecorresponding free base is obtained by introducing the hydrochlorideinto excess aqueous sodium bicarbonate, followed by chloroformextraction. The chloroform extracts, after magnesium sulfate drying, areconcentrated at reduced pressure affording the desired free base.

Step D: Preparation of 2-formyl-3-hydroxy-4,5-dihydroxymethylpyridinehydrochloride

A flask is charged with 1.14 gm. (0.03 m) lithium aluminum hydride and50 ml. anhydrous ether. After cooling a solution of 0.01 m. of thediester from Step C in 5 ml. ether is added dropwise with stirring. Thereaction mixture is then maintained under gentle reflux for 6 hours.Then the reaction mixture is cooled, and 100 ml. ice-water addeddropwise with stirring, Then carbon dioxide gas is introduced for 30minutes. The resulting solid is collected by filtration, and stirredwith 100 ml. aqueous ethanol (1:1). Carbon dioxide gas is againintroduced for 30 minutes. After filtration, the solids are washed withhot ethanol (3 × 50 ml.). All filtrates and washings are combined,acidified with hydrochloric acid, warmed for 30 minutes at 50° C, andevaporated to dryness at reduced pressure. Extraction of the residuewith hot ethanol (4 × 25 ml.), followed by filtration and evaporation,gives the crude dicarbinol.

Step E: Preparation of2-formyl-3-acetoxy-4-acetoxymethyl-5-acetoxymethypyridine

A solution of one equivalent of2-formyl-3-hydroxy-4,5-dihydroxymethylpyridine hydrochloride in 400 ml.anhydrous tetrahydrofuran is treated with four equivalents oftriethylamine and aged for one hour at room temperature. Then threeequivalents of acetic anhydride are introduced, and the reaction mixtureis aged 4 hours at room temperature. The reaction mixture isconcentrated under reduced pressure to a gum. This is treated with amixture of 300 ml. of diethyl ether and 300 ml. of distilled water.After shaking well, the layers are separated and the ether layer isdried over magnesium sulfate. After evaporation to dryness, the desiredtriacetate is obtained as a viscous oil.

Step F: Preparation of 2-vinyl-3-hydroxy-4,5-dihydroxymethylpyridinehydrochloride

A 2 liter flask is charged with one equivalent of methyltriphenylphosphonium chloride and 600 ml. of anhydrous diethyl ether.This solution is cooled to 0° C. and one equivalent of n-butyllithium inhexane is introduced over a 30 minute period under nitrogen. Whenaddition is complete, the solution is aged an additional 30 minutes at0°-5° C. Then a solution of one equivalent of2-formyl-3-acetoxy-4,5-diacetoxymethyl pyridine in 250 ml. of anhydrousether is added dropwise with stirring over a one hour period. Thereaction mixture is then aged 16 hours at room temperature, and is thencooled to 0° C. and filtered. The filtrate is concentrated to drynessunder reduced pressure and treated with a mixture of 500 ml. of 2.5 Nhydrochloric acid and 300 ml. of ethyl acetate. After shaking well, theorganic phase is separated and discarded. The aqueous phase is extractedwith 2 more 300 ml. portions of ethyl acetate and these too arediscarded. The aqueous phase is then refluxed with stirring undernitrogen for 3 hours and after cooling is poured onto excess aqueoussodium bicarbonate. The crude, solid, free base is isolated byfiltration and air dried. This crude solid is taken up into 300 ml. drytetrahydrofuran and saturated with dry hydrogen chloride at 0° C. Then300 ml. dry diethyl ether is introduced and the desired hydrochloridecrystallized. It is isolated by filration and dried in vacuo.

Step G: Preparation of2-vinyl-3-hydroxy-4-mercaptomethyl-5-hydroxymethylpyridine

The product from Step F is treated with sodium hydroxide and carbondisulfide as described in Example 1, Step C, to produce2-vinyl-3-hydroxy-4-mercaptomethyl-5-hydroxymethylpyridine.

EXAMPLE 132-Methyl-3-Hydroxy-4-Mercaptomethyl-5-Hydroxymethyl-6-Vinylpyridine StepA: Preparation of N-acryloylalanine ethyl ester

To 0.5 moles of alanine ethyl ester hydrochloride in 500 ml. of benzeneis added 0.5 moles of acryloyl chloride. To this stirred mixture isadded portionwise 0.6 moles of anhydrous sodium carbonate. The reactionmixture is then refluxed for 1 hour, stirred and additional 2 hours,filtered, and the filtrate concentrated to give N-acryloylalanine ethylester.

Step B: Preparation of 5-ethoxy-4-methyl-2-vinyloxazole

To a suspension of 1.0 mole of phosphorus pentoxide in 300 ml. of drychloroform is added dropwise with stirring a solution of 0.5 mole ofN-acryloylalamine ethyl ester. The reaction mixture is heated at gentlereflux for 5 hours and then cooled. To the cooled mixture is added withrapid stirring 750 ml. of 20% aqueous potassium hydroxide. Afterstirring at room temperature for 1 hour, the chloroform layer isseparated and the aqueous layer extracted with 2 × 200 ml. ofchloroform. The combined chloroform extracts are washed with water,dried over sodium sulfate, and concentrated in vacuo to yield5-ethoxy-4-methyl-2-vinyloxazole.

Step C: Preparation of dimethyl 2-methyl-3-hydroxy-6-vinylpyridine4,5-dicarboxylate

A mixture of 0.2 mole of dimethyl maleate and 0.1 mole of5-ethoxy-4-methyl-2-vinyloxazole are heated at 110°-115° C. for 4 hours.The reaction mixture is cooled and 20 ml. of a 25% solution of hydrogenchloride (dry) in absolute methanol added. Addition of ether to thecooled reaction mixture precipitates the hydrochloride salt of theproduct. The free base is obtained by dissolving the hydrochloride saltin a minimum volume of water, adding solid sodium bicarbonate to pH 6.5to 7.0 and extracting with chloroform. The combined chloroform extractsare dried over sodium sulfate and concentrated in vacuo to give dimethyl2-methyl-3-hydroxy-6-vinylpyridine 4,5-dicarboxylate.

Step D: Preparation of2-methyl-3-hydroxy-4,5-di(hydroxymethyl)-6-vinylpyridine

To a suspension of 0.15 moles of lithium aluminum hydride in 250 ml. ofether is added dropwise with stirring a solution of 0.05 moles ofdimethyl 2-methyl-3-hydroxy-6-vinylpyridine 4,5-dicarboxylate in 150 ml.of ether. The mixture is refluxed for 6 hours and stirred overnight atroom temperature. The reaction mixture is cooled and 100 ml. of wateradded dropwise with stirring. The resulting mixture is saturated withcarbon dioxide for 30 minutes and then filtered. The precipitate isstirred with 250 ml. of ethanol-water (1:1) and saturated again withcarbon dioxide and filtered. The solid is then extracted twice with 100ml. of boiling ethanol. The combined filtrates are evaporated to drynessin vacuo. The residue is extracted 5 times with 100 ml. of boilingethanol. The combined extracts are filtered and evaporated to dryness togive 2-methyl-3-hydroxy-4,5-di(hydroxymethyl)-6-vinylpyridine.

Step E: Preparation of2-methyl-3-hydroxy-4-mercaptomethyl-5-hydroxymethyl-6-vinylpyridine

Treatment of the product of Step D with sodium hydroxide and carbondisulfide by the procedure described in Example 1, Step C, yields2-methyl-3-hydroxy-4-mercaptomethyl-5-hydroxymethyl-6-vinylpyridine.

EXAMPLE 14 Bunte salt of2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine Step A: Preparationof 2-methyl-3-hydroxy-4-chloromethyl-5-vinyl pyridine hydrochloride

A mixture of 1.65 g. of2-methyl-3-hydroxy-4-hydroxymethyl-5-vinylpyridine hydrochloride, 1 ml.of thionyl chloride and 20 ml. of tetrahydrofuran is refluxed 6 hours.After cooling, the precipitate is collected on a filter, washed withether and dried to give 2-methyl-3-hydroxy-4-chloromethyl-5-vinylpyridine hydrochloride.

Step B: Preparation of Bunte salt of2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine

A solution of 20 g. of sodium thiosulfate pentahydrate in 15 ml. ofwater is added to a solution of 18 g. of2-methyl-3-hydroxy-4-chloromethyl-5-vinylpyridine hydrochloride in 100ml. of 50% ethanol. The mixture is heated 1 hour at 75° C., cooled andevaporated to dryness to give Bunte salt of2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine, m.p. 198°-200° C.

EXAMPLE 15 2-Methyl-3-Hydroxy-4-Mercaptomethyl-5-Vinylpyridine MixedDisulfide with penicillamine, Dihydrochloride

The Bunte salt (0.01 mole) from Example 14, 0.01 mole of penicillamineand 3 molecular equivalents of sodium hydroxide (2.5 N aqueous solution)are warmed together on a steam bath for 2 hours. After cooling themixture is extracted with 2 × 50 ml. of ethyl acetate. The extract isdried over magnesium sulfate and concentrated to dryness. The residue istaken up in tetrahydrofuran and treated with hydrogen chloride toprecipitate 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine mixeddisulfide with penicillamine, dihydrochloride.

EXAMPLE 16 2-Methyl-3-Hydroxy-5-Vinyl-4-Pyridylmethylthiophosphonic AcidStep A: Preparation of sodium2-methyl-3-hydroxy-5-vinyl-4-pyridylmethylthiophosphorothioate

Trisodium phosphorothioate (1.8 g., 0.01 mole) in water (5 ml.) is runinto a solution of 2-methyl-3-hydroxy-4-chloromethyl-5-vinylpyridinehydrochloride (0.01 mole) in water (15 ml.) at 0°. The solution isstirred overnight at 10°. The solution is diluted with methanol and thesolid sodium2-methyl-3-hydroxy-5-vinyl-4-pyridylmethylthiophosphorothioate isfiltered off.

Step B: Preparation of2-methyl-3-hydroxy-5-vinyl-4-pyridylmethylthiophosphonic acid

The product from Step A (0.01 mole) in water (40 ml.) is acidified to pH1 with dilute hydrochloric acid, and kept there for 20 minutes. Methanolis added to precipitate the subject compound as an internal salt.

EXAMPLE 17 2-Methyl-4-Mercaptomethyl-5-Vinylpyridine Step A: Preparationof 2-methyl-4-acetoxymethyl-5-hydroxymethylpyridine

2-Methyl-4,5-di(hydroxymethyl)pyridine (0.1 mole) is stirred in pyridine(50 ml.) with acetic anhydride (0.1 mole) at room temperature overnight.The pyridine is evaporated and the residue is dissolved in 10 ml. waterand extracted with 2 × 30 ml. of chloroform. After drying over magnesiumsulfate, the chloroform is evaporated and the residue is chromatographedon a silica gel column using benzene-ethanol as eluate. By thisprocedure is obtained:

1. 2-methyl-4-acetoxy-5-hydroxymethylpyridine;

2. 2-methyl-4-hydroxymethyl-5-acetoxymethylpyridine;

3. 2-methyl-4,5-di(acetoxymethyl)pyridine.

Step B: Preparation of 2-methyl-4-acetoxymethyl-5-formylpyridine

This product is prepared by oxidation of2-methyl-4-acetoxymethyl-5-hydroxymethylpyridine (from Step A) withchromium trioxide in pyridine by the procedure substantially asdescribed in Example 11, Step A.

Step C: Preparation of 2-methyl-4-acetoxy-5-vinylpyridine

This product is prepared from the product of Step B by means of a Wittigreaction employing triphenylmethylphosphorium bromide as reagent and theprocedure substantially as described in Example 1, Step. A.

Step D: Preparation of 2-methyl-4-hydroxymethyl-5-vinylpyridine

The product from Step C (0.05 mole) is stirred in aqueous alcoholicsolution (1:1) of 2.5 N sodium hydroxide (40 ml.) at room temperaturefor 4 hours. The mixture is concentrated to dryness. The residue isdissolved in 20 ml. of water, acidified with acetic acid and neutralizedwith sodium bicarbonate. The precipitate is collected and dried to give2-methyl-4-hydroxymethyl-5-vinylpyridine.

Step E: Preparation of 2-methyl-4-mercaptomethyl-5-vinylpyridine

The above product, 0.1 mole, is dissolved in 100 ml. of tetrahydrofuranand 0.1 mole of thionyl chloride introduced. After 3 hours reflux, thereaction mixture is cooled and the desired 4-chloromethyl intermediateis isolated by filtration.

The 4-chloromethyl compound (0.1 mole) in 100 ml. of absolute ethanol isadded dropwise to a solution of 0.35 equivalents potassium ethylxanthatein 200 ml. of water at 0°-5° C., at such a rate that the temperaturedoes not exceed 10° C. After addition, the reaction is aged one hour at5°-10° C. and 4 hours at room temperature. The reaction mixture isquenched on 150 ml. of ether and shaken well. After separation, theether layer is dried over magnesium sulfate and evaporated in vacuo toafford 4-ethylxanthatomethyl intermediate.

The xanthate in 200 ml. of tetrahydrofuran:ether (3:1 v/v) is added toexcess lithium aluminum hydride under ether and nitrogen at 0° C. over30 minutes. After stirring one hour at room temperature, it is pouredinto a mixture of tetrahydrofuran and saturated ammonium chloridesolution. The water layer is separated and extracted with 2 × 400 ml. oftetrahydrofuran. The combined tetrahydrofuran solutions are dried andevaporated to dryness to give 2-methyl-4-mercaptomethyl-5-vinylpyridine.

EXAMPLE 18 2-Methyl-4-Vinyl-5-Mercaptomethylpyridine

Employing the procedure substantially as described in Example 17, StepsB, C, D, E, but substituting for the2-methyl-4-acetoxymethyl-5-hydroxymethylpyridine used in Example 17,Step B, an equivalent amount of2-methyl-4-hydroxymethyl-5-acetoxymethylpyridine, there are producedsequentially,

2-methyl-4-formyl-5-acetoxymethylpyridine,

2-methyl-4-vinyl-5-acetoxymethylpyridine,

2-methyl-4-vinyl-5-hydroxymethylpyridine, and

2-methyl-4-vinyl-5-mercaptomethylpyridine.

EXAMPLE 19 2-Vinyl-5-Mercaptomethylpyridine Step A: Preparation ofmethyl-6-methylnicotinate

6-Methylnicotinic acid (0.1 mole) is refluxed in 100 ml. of methanolsaturated with gaseous hydrogen chloride for 1 hour and then evaporatedto dryness. The residue is stirred saturated aqueous sodium bicarbonatesolution and the product is extracted into chloroform. The chloroformextract is dried and concentrated to dryness to give methyl6-methylnicotinate.

Step B: Preparation of 2-methyl-5-hydroxymethylpyridine

Methyl 6-methylnicotinate (0.05 mole) is stirred in dry tetrahydrofuran(50 ml.) at 10° C. while solid lithium aluminum hydride (0.0125 mole) isadded over 1 hour. Water (10 ml.) is added with stirring, and themixture is concentrated to dryness. The residue is extracted severaltimes with hot isopropanol and the combined extracts are filtered andconcentrated to dryness to give 2-methyl-5-hydroxymethylpyridine.

Step C: Preparation of 2-methyl-5-acetoxymethylpyridine

2-Methyl-5-hydroxymethylpyridine (0.1 mole) is stirred in pyridine (50ml.) with acetic anhydride (0.15 ) mole) at room temperature overnight.The mixture is concentrated to dryness, and the residue is dissolved in70 ml. of water and extracted with 3 × 25 ml. of chloroform. Afterdrying over magnesium sulfate, the chloroform is concentrated to drynessto give 2-methyl-5-acetoxymethylpyridine.

Step D: Preparation of 2-methyl-5-acetoxymethylpyridine-N-oxide

2-Methyl-5-acetoxymethylpyridine (0.05 mole) is stirred in 50 ml. ofchloroform at 15° C. while chloroperbenzoic acid (0.06 mole) is addedover 10 min. The solution is extracted with saturated sodium bicarbonatesolution (3 × 20 ml.) and 2 × 20 ml. of water. The chloroform is driedover magnesium sulfate, and concentrated to dryness to give2-methyl-5-acetoxymethylpyridine-N-oxide.

Step E: Preparation of 2,5-di(acetoxymethyl)pyridine

2-Methyl-5-acetoxymethylpyridine-N-oxide (0.05 mole) is refluxed in 50ml. of acetic anhydride for two hours and then evaporated to dryness.The residue is fractionally distilled under high vacuum to obtain2,5-di(acetoxymethyl)pyridine.

Step F: Preparation of 2,5-di(hydroxymethyl)pyridine

2,5-Di(acetoxymethyl)pyridine (0.05 mole) is reduced with lithiumaluminum hydride (0.025 mole) in tetrahydrofuran (50 ml.) at 0° C. withstirring. After one hour, water is added to decompose excess hydride,and the mixture is concentrated to dryness. The residue is extractedwith hot isopropanol (2 × 60 ml.) and the extract is concentrated todryness to give 2,5-di(hydroxymethyl) pyridine.

Step G: Preparation of 2-formyl-5-hydroxymethylpyridine

2,5-Di(hydroxymethyl)pyridine (10 g.) in 300 ml. of hot chloroform istreated with 100 g. of manganese dioxide. After 1/2 hour of stirring,the mixture is filtered and the filtrate is evaporated to dryness togive 2-formyl-5-hydroxymethylpyridine.

Step H: Preparation of 2-formyl-5-chloromethylpyridine hydrochloride

2-Formyl-5-hydroxymethylpyridine (0.1 mole) in 100 ml. oftetrahydrofuran is treated with 0.11 mole of thionyl chloride, and themixture is refluxed 3 hours. The product,2-formyl-5-chloromethylpyridine hydrochloride is collected by filtrationfrom the cooled reaction mixture.

Step I: Preparation of 2-di(methoxy)methyl-5-chloromethylpyridinehydrochloride

A mixture of 0.1 mole of 2-formyl-5-chloromethyl pyridine hydrochlorideand 250 ml. of methanol which has been saturated with hydrogen chlorideis stirred overnight at room temperature. The reaction rixture is thenconcentrated in vacuo to give 5-chloromethyl-2-di(methoxy)methylpyridinehydrochloride.

Step J: Preparation of bis[2-formyl-5-pyridylmethyl]disulfide

A solution of 0.1 mole of 2-di(methoxy)methyl-5-chloromethylpyridine inabsolute alcohol (150 ml.) is added dropwise at 10°-15° C. over 20minutes, to a suspension of 6 g. of sodium sulfide (Na₂ S₂) in 50 ml. ofabsolute alcohol. The mixture stirred at room temperature for 1/2 hour,then 15 min. at 40°-50° C. and poured into 800 ml. of water. The mixtureis extracted with ether and the extract is dried over magnesium sulfateand concentrated to an oil. The oil is dissolved in 80 ml. of 1 Nhydrochloric acid and heated for 2- min. at 40° C. The mixture iscooled, adjusted to pH 7 with sodium bicarbonate and extracted withethylacetate. The extract is dried over magnesium sulfate andconcentrated to dryness to give bis[2-formyl-5-pyridylmethyl]disulfide.

Step K: Preparation of bis[2-vinyl-5-pyridylmethyl]disulfide

Employing the process of Example 1, Step A, using as starting materialsbis[2-formyl-5-pyridylmethyl]disulfide and triphenylmethylphosphoniumbromide, there is produced bis[2-vinyl-5-pyridylmethyl]disulfide.

Step L: Preparation of 2-Vinyl-5-mercaptomethylpyridine

To a suspension of 0.2 gm. of lithium aluminum hydride in 100 ml. of drytetrahydrofuran was added 0.004 mole ofbis[2-vinyl-5-pyridylmethyl]disulfide. The reaction mixture was stirredfor 3 hours at 0°-5°. At this time there was added to the reactionmixture 100 ml. of benzene, 50 ml. of water, and 20 gm. ammoniumchloride. The organic layer was separated and the aqueous extracted 2times with 50 ml. of benzene. The combined benzene extracts were washedwell with water, dried over sodium sulfate, and concentrated in vacuo.Chromatography on silica gel (250 gm.) and elution with ether gave2-vinyl-5-mercaptomethylpyridine.

EXAMPLE 20 2-Methyl-3-Hydroxy-4-Mercaptomethyl-5-Vinylpyridine-N-OxideHydrochloride Step A: Preparation of 3,4α-di-O-isopropylidene derivativeof pyridoxine N-oxide

The 3,4α-di-O-isopropylidene derivative of pyridoxine (0.05 mole) isstirred in 50 ml. of chloroform at 15° C. while m-chloroperbenzoic acid(0.06 mole) is added over 10 minutes. The solution is extracted withsaturated sodium bicarbonate solution (3 + 20 ml.) and water (2 × 20ml.). The chloroform is dried over magnesium sulfate and concentrated todryness to give 3,4α-di-O-isopropylidene derivative of pyridoxineN-oxide.

Step B: Preparation of 3,4α-di-O-isopropylidene derivative ofZ-methyl-3-hydroxy-4-hydroxymethylpyridine-5-aldehyde-N-oxide

To 75 ml. of dry methylene chloride containing 4.75 ml. of dry pyridineis added with stirring and cooling 2.96 g. of chromium trioxide. Themixture is aged 20 minutes at room temperature and then treated with asolution of 1 g. of the product from Step A in 25 ml. of dry methylenechloride over 15 minutes. After one hour at room temperature, themixture is filtered, and the residue washed with 2 × 10 ml. of methylenechloride. The combined filtrates are extracted with 3 × 50 ml. of 5%(w/v) aqueous sodium hydroxide solution, dried over magnesium sulfateand evaporated to dryness to give 3,4α-di-O-isopropylidene derivative of2-methyl-3-hydroxy-4-hydroxymethylpyridine-5-aldehyde-N-oxide.

Step C: Preparation of2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine-N-oxidehydrochloride

By the procedure of Example 1, Steps A, B, and C, using as startingmaterial 3,4α-di-O-isopropylidene derivative of2-methyl-3-hydroxy-4-hydroxymethylpyridine-5-aldehyde-N-oxide andtriphenylmethylphosphonium bromide, there is produced in sequence:

3,4α-di-O-isopropylidene derivative of2-methyl-3-hydroxy-4-hydroxymethyl-5-vinylpyridine-N-oxide,

2-methyl-3-hydroxy-4-hydroxymethyl-5-vinylpyridine-N-oxidehydrochloride, and

2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine-N-oxidehydrochloride.

EXAMPLE 21 Bis[2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl]disulfide

2-Methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine hydrochloride (9 g.)is dissolved in 50 ml. water and treated with 2 N ammonium hydroxide toabout pH 9. Air is bubbled through the solution for 24 hours. Theprecipitated bis[2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl]disulfide iscollected on a filter and dried, m.p. 178°-180° (dec.).

EXAMPLE 22 Bis[2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl]disulfide

2-Methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine hydrochloride (4.36g.) was dissolved in 40 ml. of water at 2°-7° C. under a nitrogenatmosphere. To this solution there was added 2.0 ml. of 30% hydrogenperoxide over 2 mins. while maintaining the temperature at 2°-7° C.After 30 mins. stirring at this temperature, the mixture was filteredand, under nitrogen, the filtrate was stirred with excess saturatedsodium bicarbonate solution at 2° C. for 10 minutes. The mixture wasfiltered quickly and the filter cake was washed with 2 × 40 ml. ofacetonitrile. The solids were dried over phosphorus pentoxide to give1.5 g. of bis[2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl]disulfide,m.p. >300°. The monohydrate has m.p. 178°-180° C.

EXAMPLE 23 2-Methyl-3-Hydroxy-4-Mercaptomethyl-5-Vinylpyridine Step A:Preparation of 2-methyl-3-hydroxy-4-benzoylthiomethyl-5-vinylpyridine

To a stirred solution of 65 g. of2-methyl-3-hydroxy-4-chloromethyl-5-vinylpyridine in 1 liter of ethanolunder nitrogen there was added 96 g. of potassium thiobenzoate in 200ml. of water over 30 minutes. After 1 hour, the ethanol was evaporatedat 40° C. and the aqueous solution was extracted with 4 × 300 ml. ofethyl acetate. The extract was washed with 1 × 75 ml. of water, driedover magnesium sulfate and concentrated to dryness to give2-methyl-3-hydroxy-4-benzoylthiomethyl-5-vinylpyridine.

Step B: Preparation of2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine

A mixture of 1 g. of2-methyl-3-hydroxy-4-benzoylthiomethyl-5-vinylpyridine, 10 ml. oftetrahydrofuran, and 10 ml. of 2.5 N aqueous sodium hydroxide was agedat room temperature overnight. The solution was acidified to about pH 6with hydrochloric acid and then adjusted to pH 7.5 with solid sodiumbicarbonate. The mixture was extracted with 3 × 100 ml. of ethylacetate: isopropanol (9:1 v/v). The extract was dried over magnesiumsulfate and concentrated to give2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine.

EXAMPLE 24 2-Methyl-3-Hydroxy-4-Mercaptomethyl-5-Vinylpyridine

2-Methyl-3-hydroxy-4-hydroxymethyl-5-vinylpyridine, 0.1 mole, isdissolved in 100 ml. of tetrahydrofuran and 0.1 mole of thionyl chlorideintroduced. After 3 hours reflux, the reaction mixture is cooled and thedesired 4-chloromethyl intermediate is isolated by filtration.

The 4-chloromethyl compound (0.1 mole) in 100 ml. of absolute ethanol isadded dropwise to a solution of 0.35 equivalents potassium ethylxanthatein 200 ml. of water at 0°-5° C., at such a rate that the temperaturedoes not exceed 10° C. After addition, the reaction is aged one hour at5°-10° C. and 4 hours at room temperature. The reaction mixture isquenched on 150 ml. of ether and shaken well. After separation, theether layer is dried over magnesium sulfate and evaporated in vacuo toafford 4-ethylxanthatomethyl intermediate.

The xanthate in 200 ml. of tetrahydrofuran:ether (3:1 v/v) is added toexcess lithium aluminum hydride under ether and nitrogen at 0° C. over30 minutes. After stirring one hour at room temperature, it is pouredinto a mixture of tetrahydrofuran and saturated ammonium chloridesolution. The water layer is separated and extracted with 2 × 400 ml. oftetrahydrofuran. The combined tetrahydrofuran solutions are dried andevaporated to dryness to give2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine.

EXAMPLE 25 2-Methyl-3-Hydroxy-4-Mercaptomethyl-5-VinylpyridineHydrochloride Step A: Preparation of2-methyl-3-hydroxy-4-isothioureidomethyl-5-vinylpyridine

A mixture of 21.0 g. of2-methyl-3-hydroxy-4-chloromethyl-5-vinylpyridine, 6.74 g. of thiourea,and 200 ml. of ethanol was refluxed 3 hours. The cooled mixture wasfiltered and the solids were washed with ether to give2-methyl-3-hydroxy-4-isothioureidomethyl-5-vinylpyridine hydrochloride.

Step B: Preparation of2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine hydrochloride

A mixture of 9.0 g. of the isothioureido compound of Step A, and 60 ml.of 6.5% (w/v) potassium hydroxide was refluxed 4 hours. A black solidwas filtered off, and the filtrate was acidified with acetic acid andevaporated to dryness. The residue was extracted with 40 ml. of waterand 200 ml. of ether. The aqueous phase was separated, acidified withconcentrated hydrochloric acid, basified with sodium bicarbonatesolution and extracted with ethyl acetate. Evaporation to dryness gave2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine hydrochloride.

EXAMPLE 26 2-Methyl-3-Hydroxy-4-Mercaptomethyl-5-Vinylpyridine

The isothioureido compound from Example 25, Step A, (0.1 mole) in 200ml. of tetrahydrofuran:ether (3:1 v/v) is added to excess lithiumaluminum hydride under ether and nitrogen at 0° C. over 30 minutes.After stirring one hour at room temperature, it is poured into a mixtureof tetrahydrofuran and saturated ammonium chloride solution. The waterlayer is separated and extracted with 2 × 400 ml. of tetrahydrofuran.The combined tetrahydrofuran solutions are dried and evaporated todryness to give 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine.

EXAMPLE 27 2-Methyl-3-Hydroxy-4-Mercaptomethyl-5-Vinylpyridine

The Bunte salt of 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine(0.1 mole) in 200 ml. of tetrahydrofuran:ether (3:1 v/v) is added toexcess lithium aluminum hydride under ether and nitrogen at 0° C. over30 minutes. After stirring one hour at room temperature, it is pouredinto a mixture of tetrahydrofuran and saturated ammonium chloridesolution. The water layer is separated and extracted with 2 × 400 ml. oftetrahydrofuran. The combined tetrahydrofuran solutions are dried andevaporated to dryness to give2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine.

EXAMPLE 28 Bis[2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl]Disulfide

The xanthate product (0.05 mole) from Example 24 in 50 ml. ofconcentrated ammonium hydroxide and 100 ml. of ethanol is stirredovernight at room temperature. The oily residue is extracted into 2 ×100 ml. of methylene chloride and dried over magnesium sulfate. Thesolution is filtered and treated with dry gaseous hydrogen chloride at0° C. The precipitate is collected on a filter and dried to givebis[2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl]disulfide,dihydrochloride.

EXAMPLE 29 Bis[2-Methyl-3-Hydroxy-5-Vinyl-4-Pyridylmethyl]DisulfideDihydrochloride

The Bunte salt of 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine(0.1 mole) was refluxed 18 hours with 1 N sulfuric acid. This wasconcentrated to dryness, the residue was taken up in isopropanol,filtered, and again evaporated to an oil. The oil was treated withaqueous sodium bicarbonate solution. The resulting solid was collected,dissolved in isopropanol and treated with gaseous hydrogen chloride.Addition of ether caused crystallization ofbis[2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl]disulfidedihydrochloride.

EXAMPLE 30 2-Methyl-3-Hydroxy-4-Mercaptomethyl-5-Vinylpyridine

To a suspension of 0.2 gm. of lithium aluminum hydride in 100 ml. of drytetrahydrofuran was added 0.004 mole ofbis[2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl]-disulfide. The reactionmixture was stirred for 3 hours at 0°-5°. At this time there was addedto the reaction mixture 100 ml. of benzene, 50 ml. of water, and 20 gm.ammonium chloride. The organic layer was separated and the aqueousextracted 2 times with 50 ml. of benzene. The combined benzene extractswere washed well with water, dried over sodium sulfate, and concentratedin vacuo. Chromatography on silica gel (250 gm.) and elution with ethergave 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine.

EXAMPLE 31 o-Carboxyphenyl 2-methyl-3-hydroxy-5-vinylpyridin-4-yl-methylDisulfide

To a solution of 0.02 moles of o-carboxyphenylo-carboxybenzenethiolsulfonate in 200 ml. of 95% ethanol is added 0.02moles of fine powdered2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine. The reactionmixture is stirred overnight at room temperature and the resultingprecipitate filtered to yield o-carboxyphenyl2-methyl-3-hydroxy-5-vinylpyridin-4-ylmethyl disulfide.

Similarly prepared is o-carboxyphenyl2-methyl-3-hydroxy-5-ethynylpyridin-4-ylmethyl disulfide.

EXAMPLE 32S,S'-bis(2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl)-carbonodithioateDihydrochloride

To an ice cooled solution of 4.5 gm. of2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine in 50 ml. of drypyridine is added dropwise 10 ml. of a 12.5% solution of phosgene isbenzene. The reaction mixture is allowed to come to room temperature andstirred for three hours after which time it is concentrated in vacuo.The residue is extracted between benzene and saturated sodiumbicarbonate solution. The benzene layer is separated, washed with water,dried over sodium sulfate and concentrated in vacuo. The residue ischromatographed on 250 gm. of silica gel. Elution with ether givesS,S'-bis(2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl)carbonodithioatedihydrochloride.

Similarly prepared isS,S'-bis(2-methyl-3-hydroxy-5-ethynyl-4-pyridylmethyl)carbonodithioatedihydrochloride.

EXAMPLE 33 S,S'-bis(2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl)1,3-benzenedicarbothioate

To a solution of 4.5 gm. (0.02 mole) of2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine in 50 ml. ofpyridine and 50 ml. of chloroform is added dropwise with stirring asolution of 2.0 gm. (0.01 mole) of isophthaloyl dichloride in 50 ml. ofchloroform. The reaction mixture is stirred overnight at roomtemperature and then concentrated in vacuo. The residue is extractedbetween benzene and saturated sodium bicarbonate solution. The benzenelayer is separated, washed with water, dried over sodium sulfate andconcentrated in vacuo to give an oil. Chromatography on 1,000 gm. ofsilica gel and elution with ether affordsS,S'-bis(2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl)1,3-benzenedicarbothioate.

Similarly prepared isS,S'-bis(2-methyl-3-hydroxy-5-ethynyl-4-pyridylmethyl)1,3-benzenedicarbothioate.

EXAMPLE 34 EthylN-(2-methyl-3-hydroxy-5-vinyl-4-pyridylmethylthiocarbonyl)glycinate

To a well stirred mixture of 20 ml. of 12.5% phosgene in benzene and 50ml. of benzene is added dropwise a solution of 2.5 gm. (0.01 moles) of2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine in 25 ml. ofbenzene. The reaction mixture is stirred for 3 hours and then purgedwith nitrogen for 1 hour to remove any unreacted phosgene. The reactionmixture is then concentrated in vacuo to give a gummy solid. To theabove is added 5.6 gm. (0.04 moles) of ethyl glycinate and 100 ml. ofdry dioxane. The mixture is stirred and 6 ml. of triethylamine added.After stirring overnight at room temperature, the mixture isconcentrated in vacuo and the residue extracted between ether andsaturated sodium bicarbonate solution. The ether layer is separated,washed with water, dried over sodium sulfate and concentrated to givecrude product. Chromatography on 900 gm. of silica gel and elution withether gives ethylN-(2-methyl-3-hydroxy-5-vinyl-4-pyridylmethylthiocarbonyl)-glycinate.

Similarly prepared is ethylN-(2-methyl-3-hydroxy-5-ethynyl-4-pyridylmethylthiocarbonyl)glycinate.

EXAMPLE 35 N,N'-Diethyl2-methyl-3-hydroxy-5-vinylpyridin-4-yl-methylsulfenamide

To a suspension of 9.5 gm. of lead thiocyanate in 200 ml. of dry etherwhich had been cooled to 0°-5°, is added dropwise 3.7 gm. of brominedissolved in 25 ml. of carbon tetrachloride. The reaction mixture isstirred for 30 minutes after the addition is complete. The supernatantcontaining the thiocyanogen is decanted into a 1 liter flask equippedwith a mechanical stirrer and ether is added to make 500 ml. ofsolution. A solution of 4.5 gm. of2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine in 50 ml. of etheris added dropwise. A heavy precipitate forms immediately and thereaction mixture is stirred for 30 minutes after the addition iscomplete. Diethylamine (15 ml.) is then added and the reaction mixtureallowed to come to room temperature. After 1 hour 200 ml. of benzene and250 ml. of saturated sodium bicarbonate are added. The organic layer isseparated, washed with water, dried over sodium sulfate and concentratedto give an oil. Chromatography on 600 gm. of silica gel and elution with50% ether in petroleum ether gives N,N'-diethy.2-methyl-3-hydroxy-5-vinylpyridin-4-ylmethylsulfenamide as an oil.

Similarly prepared is N,N-diethyl2-methyl-3-hydroxy-5-ethynylpyridin-4-ylmethylsulfenamide.

EXAMPLE 364-Dimethylaminocarbonylthiomethyl-3-Hydroxy-2-Methyl-5-Vinylpyridine

To a mixture of 7.4 gm. (0.04 m) of2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine in 50 ml. drypyridine and 50 ml. of chloroform is added dropwise with stirring asolution of 3.25 gm. (0.3 m) of dimethylcarbamoyl chloride in 50 ml. ofchloroform.

The reaction mixture is stirred for 3 hours after the addition iscompleted, then concentrated in vacuo. The residue is extracted betweenether-benzene 1:1 and saturated sodium bicarbonate solution. The organicphase is separated, washed well with water, dried over sodium sulfate,and concentrated in vacuo to give crude material. Chromatography on 900gm. of silica gel gives4-dimethylaminocarbonylthiomethyl-3-hydroxy-2-methyl-5-vinylpyridine.

Similarly prepared is4-dimethylaminocarbonylthiomethyl-3-hydroxy-2-methyl-5-ethynylpyridine.

EXAMPLE 37 S,S'-Bis(2-methyl-3-hydroxy-5-vinyl-4-4-pyridylmethyl)1,4-piperazinedicarbothioate Dihydrochloride

To a solution of 4.50 gm. (0.02 m) of2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine in 50 ml. ofpyridine and 50 ml. of chloroform is added all at once as a solid 2.1gm. (0.01 m) of N,N'-dichlorocarbonyl piperazine. The reaction mixtureis then stirred at room temperature for 4 hours, concentrated in vacuoand extracted between chloroform and saturated sodium bicarbonatesolution. The aqueous layer is separated and extracted two times withchloroform. The combined chloroform extracts are washed with water,dried and concentrated to an oil which gradually crystallizes.Recrystallization from methanol givesS,S'-bis(2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl)1,4-piperazinedicarbothioate dihydrochloride.

Similarly prepared isS,S'-bis(2-methyl-3-hydroxy-5-ethynyl-4-pyridylmethyl)1,4-piperazinedicarbothioate dihydrochloride.

EXAMPLE 38 2-Methyl-3-Hydroxy-4-Carbamoylthiomethyl-5-Vinylpyridine

Employing the procedure of Example 34 but substituting for the ethylglycinate used therein, an equivalent amount of ammonia, there isproduced 2-methyl-3-hydroxy-4-carbamoylthiomethyl-5-vinylpyridine.

EXAMPLE 392-Methyl-3-Hydroxy-4-Mercaptomethyl-5-(2,2-dichlorovinyl)pyridineHydrochloride Step A: Preparation of5-(2,2-dichlorovinyl)-2,2,8-trimethyl-4H-1,3-dioxino[4,5-c]pyridine

To a well stirred ice-cooled mixture of 0.1 mole of triphenylphosphineand 0.1 mole of potassium t-butoxide in 250 ml. of heptane is added overthirty minutes a mixture of 0.1 mole of chloroform in 200 ml. ofhaptane. The resulting mixture is concentrated in vacuo at 15°-20° to avolume of about 100 ml. and a solution of 0.1 mole of2,2,8-trimethyl-4H-1,3-dioxino[4,5-c]pyridine-5-carboxaldehyde in 250ml. of heptane is added. The reaction mixture was heated at 40°-50° for5 hours, then cooled, filtered, and concentrated in vacuo to give crudeproduct. Chromatography on silica gel and elution with ether-petroleumether (10-50%) gives pure5-(2,2-dichlorovinyl)-2,2,8-trimethyl-4H-1,3-dioxino-[4,5-c]pyridine.

Step B: Preparation of2-methyl-3-hydroxy-4-mercaptomethyl-5-(2,2-dichlorovinyl)pyridinehydrochloride

Employing the procedure of Example 1, Steps B and C, for hydrolysis ofthe isopropylidene group and formation of the mercapto group, there isproduced2-methyl-3-hydroxy-4-mercaptomethyl-5-(2,2-dichlorovinyl)-pyridinehydrochloride.

When dichlorofluoromethane is used in place of chloroform in Step A ofthe above procedure, there is obtained5-(2-chloro-2-fluorovinyl)-2,2,8-trimethyl-4H-1,3-dioxino[4,5-c]pyridine,which upon hydrolysis and treatment with carbon disulfide as in Step B,there is produced2-methyl-3-hydroxy-4-mercaptomethyl-5-(2-chloro-2-fluorovinyl)pyridinehydrochloride.

EXAMPLE 402-Methyl-3-Hydroxy-4-Mercaptomethyl-5-(2,2-difluorovinyl)pyridineHydrochloride Step A: Preparation of5-(2,2-difluorovinyl)-2,2,8-trimethyl-4H-1,3-dioxino[4,5-c]pyridine

A mixture of 0.1 mole of2,2,8-trimethyl-4H-1,3-dioxino[4,5-c]pyridine-5-carboxaldehyde, 0.11mole of triphenylphosphine and 0.11 mole of sodium chlorodifluoroacetatein 100 ml. of diglyme is heated under nitrogen at 90° for 24 hours. Thereaction mixture is then filtered and concentrated in vacuo.Chromatography of the residue on silica gel and elution withetherpetroleum ether (10-50%) gives5-(2,2-difluorovinyl)-2,2,8-trimethyl-4H-1,3-dioxino[4,5-c]pyridine.

Step B: Preparation of2-methyl-3-hydroxy-4-mercaptomethyl-5-(2,2-difluorovinyl)pyridinehydrochloride

Employing the procedure of Example 1, Steps B and C, for hydrolysis ofthe isopropylidene group and formation of the mercapto group, there isproduced2-methyl-3-hydroxy-4-mercaptomethyl-5-(2,2-difluorovinyl)pyridinehydrochloride.

EXAMPLE 41 Preparation of the compound of formula: ##STR23##

Thiamine-S-monooxide is suspended in 120 ml. of water 1.83 g. of2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine is added over 5 min.After stirring for 1 hour, the mixture is filtered and the filtrate isextracted with n-butanol. The extract is washed with water and driedover magnesium sulfate. The dried solution is acidified with 48%hydrobromic acid in acetic acid, and evaporated to dryness. The residueis recrystallized from ethanol to give the desired product.

EXAMPLE 42 Preparation of Mixed Disulfides

Employing the procedure of Example 15, but substituting for thepenicillamine used therein, an equivalent amount of ethylmercaptan,allylmercaptan, benzylmercaptan, and thiophenol, there is producedrespectively (2-methyl-3-hydroxy-5-vinylpyridyl-4-methyl)(ethyl)disulfide, (2-methyl-3-hydroxy-5-vinylpyridyl-4-methyl)(allyl)disulfide, (2-methyl-3-hydroxy-5-vinylpyridyl-4-methyl)(benzyl)disulfide, and (2-methyl-3-hydroxy-5-vinylpyridyl-4-methyl)(phenyl)disulfide.

EXAMPLE 43 8-Methyl-2-Oxo-5-Vinyl-4H-1,3-Thioxino[4,5-c]Pyridine

To a mixture of 0.01 mole of2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine in 50 ml. chloroformand 50 ml. pyridine is added at 0° to 5° a solution of 0.022 moles ofphosgene in benzene. The reaction mixture is allowed to warm to roomtemperature and is stirred overnight. The reaction mixture is thenconcentrated in vacuo and excess saturated sodium bicarbonate solutionis added. The resulting solid is collected by filtration. Chromatographyon silica gel and elution with methanol in chloroform (1-5%) gives8-methyl-2-oxy-5-vinyl-4H-1,3-thioxion[4,5-c]pyridine.

When thiophosgene is used in place of phosgene in the above example,8-methyl-2-thiono-4H-1,3-dioxino[4,5-c]pyridine is obtained.

EXAMPLE 44 Sodium(2-methyl-3-hydroxy-5-vinyl-4-pyridyl) MethylTrithiocarbonate

2-Methyl-3-hydroxy-4-chloromethyl-5-vinylpyridine (20 g.) is suspendedin water/methanol (100:25 v/v) and treated with disodiumtrithiocarbonate (33%) (45 g.). The mixture is stirred at 50° C. for 4hours under nitrogen and adjusted to pH 6.2-6.5 with dilute acid. Theprecipitate is recrystallized from DMF/water to givesodium(2-methyl-3-hydroxy-5-vinyl-4-pyridyl) methyl trithiocarbonate.

EXAMPLE 45 Bis[2-methyl-3-hydroxy-5-vinylpyridyl-4-methyl]Trithiocarbonate

To a solution of 2-methyl-3-hydroxy-4-chloromethyl-5-vinylpyridine (9g.) in methanol (100 ml.) is added 22% sodium trithiocarbonate (17.5ml.) at 20° C. The mixture is kept at 20° C. for 3 hours. Theprecipitate is collected, washed with water and hot ethanol, and driedand recrystallized from DMF to givebis[2-methyl-3-hydroxy-5-vinylpyridyl-4-methyl]trithiocarbonate.

EXAMPLE 46 2-Methyl-3-Hydroxy-4-Mercaptomethyl-5-VinylpyridineHydrochloride

The product from Example 49 (10 g.), methanol, (200 ml.) and 10% NaOHsolution (50 ml.) are refluxed for 10 hours. The mixture is neutralizedto pH 5-7 with dilute hydrochloric acid, and extracted with ethylacetate. The extract is concentrated to dryness, and the residue ischromatographed on silica gel by elution with ethyl acetate. The ethylacetate is concentrated to dryness, the residue is taken up in THF andtreated with gaseous hydrogen chloride to precipitate2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine hydrochloride.

EXAMPLE 47S,S'-bis[2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl]-1,3-Propylenedicarbothioate

Employing the procedure of Example 33, but sustituting for theisophthaloyldichloride used therein, an equilvalent amount of glutaroylchloride, there is producedS,S'-bis[2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl]-1,3-propylenedicarbothioate.

Similarly, by employing oxalyl chloride, malonoyl chloride, succinoylchloride or pentane dicarbonyl chloride, there are producedrespectively:

S,s'-bis[2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl]dicarbothioate.

S,s'-bis[2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl]-methylenedicarbothioate.

S,s'-bis[2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl]-1,2-ethylenedicarbothioate,and

S,s'-bis[2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl]-1,5-pentamethylenedicarbothioate.

EXAMPLE 48 4-Ethoxycarbonylmethylthiomethyl-3-Hydroxy-2-Methyl-5-VinylPyridine

To an ice cold mixture of 0.01 mole of ethylmercapto acetate and 0.02mole of sodium ethoxide in 100 ml. ethanol under nitrogen is added asolution of 4-bromo-3-hydroxy-2-methyl-5-vinylpyridine hydrobromide in50 ml. of ethanol. The reaction mixture is stirred overnight at roomtemperature, concentrated in vacuo and taken up between ethyl acetateand water. The organic layer is separated, washed well with water, driedand concentrated Chromatography of the residue on silica gel-elutionwith ether-petroleum ether 10-50% gives4-ethoxycarbonylmethylthiomethyl-3-hydroxy-2-methyl-5-vinyl pyridine.

EXAMPLE 494-(2-Amino-2-carboxyethylthiomethyl)-3-Hydroxy-2-Methyl-5-Vinylpyridine

Using 0.01 mole of cysteine and 0.03 moles of sodium methoxide in theprocedure of Example 48 gives, after appropriate workup,4-(2-amino-2-carboxyethylthiomethyl)-3-hydroxy-2-methyl-5-vinylpyridine.

EXAMPLE 50 Bis[2-Methyl-3-Hydroxy-5-Vinylpyridine-4-Methyl]Disulfide

To a mixture of 0.035 mole of sodium sulfide nonahydrate and 0.034 moleof S in 50 ml. of water is added with stirring 0.02 moles of4-bromomethyl-3-hydroxy-2-methyl-5-vinylpyridine hydrobromide in 50 ml.H₂ O. The reaction mixture is stirred overnight and then filtered toisolate crude product and sulfur. The precipitate is extracted with 8%aqueous hydrochloric acid, filtered, and the filtrate then neutralizedwith sodium bicarbonate. The resulting precipitate is filtered to givebis[2-methyl-3-hydroxy-5-vinylpyridin-4-methyl]disulfide.

EXAMPLE 51 Bis[2-methoxy-3-hydroxy-5-vinylpyridyl-4-methyl]trisulfideStep A: Preparation of2-methyl-3-benzyloxy-4-hydroxymethyl-5-vinylpyridine

To a mixture of 0.1 mole3-hydroxy-4-hydroxymethyl-2-methyl-5-vinylpyridine in 500 ml. of acetoneand 25 gm. potassium carbonate is added 0.11 mole of benzyl chloride.The reaction mixture is stirred overnight, filtered, and the acetoneremoved in vacuo to yield2-methyl-3-benzyloxy-4-hydroxymethyl-5-vinylpyridine.

Step B: Preparation of2-methyl-3-benzyloxy-4-chloromethyl-5-vinylpyridine

To a solution of 0.1 mole of3-benzyloxy-4-hydroxymethyl-2-methyl-5-vinylpyridine in 500 ml. ofbenzene is added dropwise with cooling a solution of 0.11 mole ofthionyl chloride in 50 ml. benzene. The reaction mixture is stirred for1 hour and then filtered to give2-methyl-3-benzyloxy-4-chloromethyl-5-vinylpyridine.

Step C: Preparation of2-methyl-3-benzyloxy-4-mercaptomethyl-5-vinylpyridine

To a well stirred solution of 0.11 mole of thiourea in 250 ml. methanol,under N₂ is added 0.1 mole of3-benzyloxy-4-chloromethyl-2-methyl-5-vinylpyridine hydrochloride. Themixture is refluxed for 1 hour and then cooled. A solution of 0.4 moleof sodium hydroxide in 50 ml. of water is added, and the resultingmixture refluxed for 30 minutes. After concentration in vacuo thereaction mixture is taken up between benzene and water and enough aceticacid added to neutralize the mixture. The organic layer is separated,washed well with water, dried, and concentrated to give 2-methyl-3 l-benzyloxy-4-mercaptomethyl-5-vinylpyridine.

Step D: Preparation ofbis[2-methyl-3-benzyloxy-5-vinylpyridyl-4-methyl]trisulfide

To 0.01 mole of sodium hydride in 50 ml. dry dimethylformamide undernitrogen at 0°14 5° is added 0.01 mole of2-methyl-3-benzyloxy-4-mercaptomethyl-5-vinylpyridine in 10 ml. ofdimethylformamide. When the evolution of hydrogen has ceased, 0.005 moleof sulfur dichloride is added. The reaction mixture is stirredovernight, poured into benzene-ice water, dried and concentrated.Chromatography on silica gel and elution with ether-petroleum ether(10-80%) givesbis[2-methyl-3-benzyloxy-5-vinylpyridyl-4-methyl]trisulfide.

Step E: Preparation ofbis[2-methoxy-3-hydroxy-5-vinylpyridyl-4-methyl]trisulfide

A mixture of 0.01 molebis(3-benzyloxy-2-methyl-5-vinylpyridyl-4-methyl)trisulfide in 10 ml.concentrated hydrochloric acid and 20 ml. acetic acid is heated 2 hoursat 60°. The reaction mixture is concentrated in vacuo and taken upbetween benzene-ether (1:1) and saturated sodium bicarbonate solution.The organic layer is separated, washed with water, dried andconcentrated in vacuo to yieldbis[2-methoxy-3-hydroxy-5-vinylpyridyl-4-methyl]trisulfide.

EXAMPLE 52 Bis [2-Methyl-3-Hydroxy-5-Vinylpyridyl-4-Methyl]Tetrasulfide

Following the procedure substantially as described in Example 51, StepsD and E, but substituting for the sulfur dichloride used in Step D, anequimolar amount of sulfur monochloride, there is produced in turn,bis[2-methyl-3-benzyloxy-5-vinylpyridyl-4-methyl]tetrasulfide andbis[2-methyl-3-hydroxy-5-vinylpyridyl-4-methyl]tetrasulfide.

EXAMPLE 53 Bis [2-Methyl-3-Hydroxy-5-Vinylpyridyl-4-Methyl]DisulfideStep A: Preparation of2,2,8-trimethyl-4H-m-dioxino-[4,5-C]pyridine-5-methanol

Materials:

1700 ml. acetone

500 gm. pyridoxine hydrochloride

˜825 gm. anhydrous hydrogen chloride

2360 gm. 50% w/w sodium hydroxide solution

Into a 5 liter, 3-necked flask fitted with a thermometer, stirrer, andgas inlet tube was charged 500 gm. (2.43 moles) of pyridoxinehydrochloride and 1400 ml. of acetone. The slurry was cooled to 0°-5°and anhydrous hydrogen chloride added at this temperature until a clearpale yellow solution resulted. Aged at this temperature for 1 hour.

After aging at 0°-5° for 1 hour, the solution was slowly added to anefficiently cooled and agitated mixture of 2360 gm. of 50% w/w NaOH(29.5 moles) and 3 liters of water holding the temperature below 35°.

The resulting white slurry was cooled to 20°, filtered and washed with 5× 100 ml. of water. Air drying over the weekend gave 472 gm. of productmelting at 90°-94°. Washing on a funnel with acetone gave 398 gm. ofproduct melting at 90°-101° when air dried and 361 gm. (71%) melting at108°-100° when dried at 45° under vacuum.

The mother liquors from the first filtration, on standing overnight,produced 53 gm. of product which melted at 108°-110° when dried at 45°under vacuum. The total yield thus was 414 gm. of 81%.

Step B: Preparation of5-formyl-2,2,8-trimethyl-4H-m-dioxino[4,5-c]pyridine

Materials:

125.4 gm. 2,2,8-trimethyl-4-H-m-dioxino[4,5-c]pyridine-5-methanol

2400 ml. benzene

250.8 gm. MnO₂ ("Activated")

300 ml. hexane

A three liter, three-necked flask was set up, equipped with an agitator,thermometer, Dean-Stark trap and condenser. To this was charged 1650 ml.of benzene and 250.8 gm. of MnO₂. The mixture was refluxed 1-1/2 hoursduring which time a total of 3.0 ml. of water was removed from the trap.The mixture was cooled to 30° and 125.4 gm. (0.600 moles) of2,2,8-trimethyl-4H-m-dioxino[4,5-c]pyridine-5-methanol from Step Aadded.

Again the mixture was refluxed drawing off 4.8 ml. (0.266 moles) ofwater over 2 hours.

The black slurry was cooled to 25° and filtered. The resulting cake waswashed with 3 × 250 ml. of benzene. The filtrate and washings werestripped to a volume of 150-200 ml. under vacuum, 200 ml. of hexaneadded and again vacuum stripped to a volume of 150-200 ml. An additional100 ml. of hexane was added and the slurry cooled to 0°-5° and aged 1hour.

The product was filtered and washed with 1 × 50 ml. of hexane. It wasdried overnight at room temperature under vacuum to give 81.60 gm.(65.6%), m.p. 61.5°-64°.

The mother liquor was stripped to a dry solid (constant weight) undervacuum to yield 24.10 gm. (19.4%), m.p. 56°-60°. Total yield 85%.

Step C: Preparation of methyltriphenylphosphonium bromide

Materials:

492 gm. triphenyl phosphine

249 gm. methyl bromide

3000 ml. benzene

To a four liter Erlenmeyer flask was charged 492 gm. of triphenylphosphine and 1200 ml. of benzene. The mixture was stirred magneticallyfor ten minutes until a clear solution resulted. Methyl bromide (249gm.) chilled to -10° was added and the flask stoppered and taped shut.The mixture was stirred overnight at room temperature.

An additional 900 ml. of benzene was added and the mixture heated to 50°while breaking up lumps. The slurry was cooled to 30°, filtered andwashed with 3 × 300 ml. of benzene.

The product was dried to constant weight at 50°-55° under vacuum.

The yield was 662 gm. (98.8%), m.p. 228°-230°.

Step D: Preparation of 5-ethenyl-3-hydroxy-2-methyl-4-pyridine methanol

Materials:

10 liters tetrahydrofuran

1455 gm. methyl triphenylphosphonium bromide

2.31 liters 1.6 M butyl lithium (in hexane)

763 gm. 5-formyl-2,2,8-trimethyl-4H-m-dioxino-[4,5-c]pyridine

12 liters benzene

185 gm. sodium bisulfite

116 ml. ethanol

6.83 liters 2.5 N hydrochloric acid (1.48 liters conc. HCl + 5.35 1water)

850 ml. 50% w/w sodium hydroxide (aq.)

To a 20 liter, 3-necked flask equipped with an agitator, thermometer,nitrogen inlet, dropping funnel and drying tube was charged 8.75 litersof tetrahydrofuran and 1,455 gm. (4.06 moles) of methyltriphenylphosphonium bromide.

Butyl lithium solution (2.31 liters of 1.6 M = 3.69 moles) in hexane wasadded over 45 minutes maintaining 25° with an ice bath. The thin yellowslurry was aged for 1.5 hours.

5-Formyl-2,2,8-trimethyl-4-H-m-dioxino[4,5-c]-pyridine (763 gm. = 3.69moles) was dissolved in 1940 ml. of dry tetrahydrofuran and a smallamount of insoluble material filtered out.

The THF solution of the aldehyde was charged to the batch over 1 hourmaintaining the temperature at 25° with an ice-bath and the resultingdeep yellow slurry aged with stirring for 1 hour.

After aging, the reaction mixture was quenched into a stirred mixture of7.75 liters of water and 7.75 liters of benzene and stirredapproximately 30 minutes or until two clear layers resulted. The waterlayer was discarded and the organic layer extracted with 7.75 liters ofwater which was also discarded. The organic layer was now extracted witha solution of 185 gm. of sodium bisulfite dissolved in 384 ml. of waterto which 116 ml. of ethanol had been added when the salt dissolved. Thebisulfite extract was also discarded.

The organic layer was extracted with 6.8 liters of 2.5 N hydrochloricacid and then the water layer back washed with 2.1 liters of benzene.

The acid solution of product was subject to approximately 28 inchesvacuum and the temperature gradually raised to 35° during which timeresidual solvents were removed and finally water began to distill. Underatmospheric pressure, the temperature of the solution was raised to 90°,held for 20 minutes, then cooled rapidly to 15°.

To the batch was added 1,330 ml. of THF and the solution slowlyneutralized to pH 4.7 ± 0.2 over a 1 hour period with approximately 850ml. of 50% w/w sodium hydroxide solution holding the temperature at 25°.The batch was seeded with 100 mg. of product and stirred 1.5 hours untilcrystallization was well under way. The pH of the mixture was nowcarefully raised over 1 hour with approximately 70 ml. of 50% sodiumhydroxide to pH 7.0 ± 0.2. The slurry was aged overnight with stirringat 25°.

The product was filtered and washed with 3 × 370 ml. of water. It wasair dried at 25° to a constant weight of 490 gm. (80.6%), melting point162°-167.5° (d).

Step E: Preparation of4,4'-dithiodimethylenebis(5-ethenyl-2-methyl-3-pyridinol)

Materials:

485 gm. 5-ethenyl-3-hydroxy-2-methyl-4-pyridine methanol

7 liters ethanol-2BA

517 gm. sodium hydroxide pellets reagent grade

590 ml. carbon disulfide

990 ml. conc. hydrochloric acid

4.5 liters ethyl acetate

˜150 ml. 50% sodium hydroxide solution

6.6 liters 2.5% sodium hydroxide solution

140 ml. 30% hydrogen peroxide

˜390 ml. 1:1 hydrochloric acid

A 12 liter, 3-necked flask was set up and equipped with an agitator,thermometer, condenser, dropping funnel and nitrogen inlet. To this wascharged 5.15 liters of ethanol-2BA and 517 gm. (12.9 moles) of sodiumhydroxide pellets. The mixture was allowed to warm to 50° to aidsolution and, when solution was complete, cooled to 25°.

To this solution was added 485 gm. (2.93 moles) of5-ethenyl-3-hydroxy-2-methyl-4-pyridine methanol. The solution wascooled at 10°-15° and 295 ml. (4.85 moles) of carbon disulfide addedover 30 minutes at 10°-15°. The batch was warmed to 25° and aged 30minutes. The mixture was again cooled to 10°-15° and an additional 295ml. of carbon disulfide added over 30 minutes at that temperature. Thebatch was then warmed to 25° and held 1 hour.

The reaction mixture was carefully heated to reflux over 1 hour and heldat reflux for 1 hour. It was then cooled to 25°, 200 gm. of Supercel wasadded, and the solids removed by filtration through two 6 inches funnelsprecoated with 50 gm. each of Supercel. The cakes were washed with atotal of 1500 ml. of ethanol-2BA.

The clear filtrate was concentrated under vacuum at a maximum batchtemperature of 30° to a volume of 2 to 2.5 liters. Four liters of waterwas added and at 5°-10° the pH adjusted to 2 ± 0.2 with approximately975 ml. of concentrated hydrochloric acid. Vacuum stripping wascontinued until a clear solution was obtained and then for an additionalthirty minutes.

To the clear solution was added 3 liters of ethyl acetate and the pHadjusted to 7 ± 0.2 by the addition of approximately 150 ml. of 50%sodium hydroxide with stirring at 20°-25°. The layers were separated andheld. The aqueous layer was extracted a second time with 1.5 liters ofethyl acetate, the layers separated, and the ethyl acetate layerscombined.

The combined ethyl acetate solution was extracted with 1 × 590 ml. of2.5% sodium hydroxide solution.

The clear combined aqueous extracts were cooled to 5°-10° and 140 ml. of30% hydrogen peroxide carefully added over 30-45 minutes.

The reaction mixture was warmed carefully to 25° and aged at thistemperature for 1 hour. Ethanol (2.5 liters) was added and the pHadjusted to 7 ± 0.2 with approximately 390 ml. of 1:1 hydrochloric acid.The slurry was aged 30 minutes and filtered. The cake was washed with atotal of 1.5 liters of 1:1 ethanol-water. The product was air dried at25° to a constant weight. Yield 427 gm. (73.3%, calculated asdihydrate), m.p. = 190°-193°.

Step F: Preparation of4,4'-dithiodimethylenebis(5-ethenyl-2-methyl-3-pyridinol)sulfatemonohydrate

In a 12 liter flask, 259 gm. of concentrated sulfuric acid (BakerAnalyzed, 95.6%) was added to 4.25 liters of water and heated to 70°. Tothis was added 425 gm. of the crude free base from the previous step(Run No. 8145-259-3) and the slurry heated to 90° where solution tookplace. The orange colored solution was treated with 42.5 gm. of NucharC-190N, aged 5 minutes at 90°-93° and filtered through a layer of 50 gm.of Supercel. The cake was washed with 2 × 100 ml. of hot 1 N H₂ SO₄solution.

The somewhat lighter colored solution was cooled immediately to roomtemperature and finally to 0°-5° where it was aged with stirring for 1hour.

The product was filtered, washed with 1 × 120 ml. of distilled water,slurried on the funnel with 1 × 200 ml. of water, and finally washedwith 1 × 120 ml. of water. The product was dried under vacuum at 25° toconstant weight. The yield was 427 gm. (83.5%); m.p. 157.5° C. (dec.).

    ______________________________________                                        Analytical data:                                                              Color:            Pale light yellow                                           M.P.:             157.5° (decomposition)                               UV.sub.303 :      351* (N/10 HCl)                                             TGA to 120°:                                                                             4.4% (Theory = 3.85%)                                       Elemental Anal.:                                                              Calculated for C.sub.18 H.sub.20 N.sub.2 O.sub.2 S.sub.2 . H.sub.2            SO.sub.4 . H.sub.2 O                                                                       Calculated     Found*                                            C            45.35          45.25                                             H             5.08           5.21                                             N             5.89           5.64                                             LC:   99.4 ± 1.0%*                                                         TLC:  One impurity and streaking (Analtech GF/16:8:1                                Spotted from 2N HCl/THF)                                                ROI:  0.02%                                                                   HM:   <10 PPM                                                                 ______________________________________                                         *Uncorrected for the 0.55% TGA over theory.                              

Step G: Preparation of4,4'-dithiodimethylenebis(5-ethenyl-2-methyl-3-pyridinol) (free base)

A run according to that described in Step F was made using 12.0 gm. ofcrude disulfide. The yield of damp cake was 17.86 gm.

A solution of 5.6 gm. of sodium bicarbonate was made in 120 ml. of waterand 120 ml. of ethanol added. By warming to 50 ° precipitatedbicarbonate redissolved.

The damp cake from above was added to the bicarbonate solution as fastas evolved carbon dioxide would allow (30 minutes) and the resultingslurry stirred at 50° for 1 hour. The slurry was cooled to roomtemperature and stirred 1 hour.

The slurry was filtered and washed with 3 × 10 ml. of water (Sulfate iontest slightly positive). After washing with an additional 1 × 10 ml. ofwater (test negative), the product was dried in a vacuum (1 mm)desiccator overnight at room temperature to constant weight.

The overall yield was 10.81 gm. (90%) of dihydrate; m.p. 197°-198° C.(dec.).

EXAMPLE 54

A mixture of 250 parts of2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine hydrochloride and 25parts of lactose is granulated with suitable water, and to this is added100 parts of maize starch. The mass is passed through a 16 mesh screen.The granules are dried at a temperature below 60° C. The dry granulesare passed through a 16 mesh screen, and mixed with 3.8 parts ofmagnesium stearate. They are then compressed into tablets suitable fororal administration.

The specific mercaptomethylpyridine used in the foregoing example may bereplaced by 25, 100, 250, or 500 parts of other mercaptoalkylpyridinesof this invention to produce tablets suitable for oral administrationaccording to the method of this invention.

EXAMPLE 55

A mixture of 50 parts of2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine hydrochloride, 3parts of the calcium salt of lignin sulfonic acid, and 237 parts ofwater is ball-milled until the size of substantially all of theparticles is less than 10 microns. The suspension is diluted with asolution containing 3 parts of sodium carboxymethylcellulose and 0.9parts of the butyl ester of p-hydroxybenzoic acid in 300 parts of water.There is thus obtained an aqueous suspension suitable for oraladministration for therapeutic purposes.

EXAMPLE 56

A mixture of 250 parts of2-methyl-3-hydroxy-4-vinyl-5-mercaptomethylpyridine, 200 parts of maizestarch, and 30 parts of alginic acid is mixed with a sufficient quantityof 10% aqueous paste of maize starch, and granulated. The granules aredried in a current of warm air, and the dry granules are then passedthrough a 16-mesh screen, mixed with 6 parts of magnesium stearate andcompressed into tablet form to obtain tablets suitable for oraladministration.

EXAMPLE 57

A mixture of 500 parts2-methyl-3-hydroxy-4-mercaptomethyl-5-ethynylpyridine, 60 parts maizestarch, and 20 parts of gum acacia is granulated with a sufficientquantity of water. The mass is passed through a 12-mesh screen, and thegranules are dried in a current of warm air. The dry granules are passedthrough a 16-mesh screen, mixed with 5 parts of magnesium stearate andcompressed into tablet form suitable for oral administration.

EXAMPLE 58

1. Tablets -- 10,000 scored tablets for oral use, each containing 500mg. of active ingredient are prepared from the following ingredients:

    ______________________________________                                                              Gm.                                                     ______________________________________                                        2-methyl-3-hydroxy-4-mercapto-                                                                        5000                                                  methyl-5-(1-propenyl)pyridine                                                 hydrochloride                                                                 Starch, U.S.P.          350                                                   Talc, U.S.P.            250                                                   Calcium stearate        35                                                    ______________________________________                                    

The powdered mercaptomethylpyridine is granulated with a 4% w./v.aqueous solution of methylcellulose U.S.P. (1500 cps.). To the driedgranules is added a mixture of the remainder of the ingredients and thefinal mixture compressed into tablets of proper weight.

2. Capsules -- 10,000 two-piece hard gelatine capsules for oral use,each containing 250 mg. of active ingredient are prepared from thefollowing ingredients:

    ______________________________________                                                              Gm.                                                     ______________________________________                                        2-methyl-3-hydroxy-4-mercapto-                                                                        2500                                                  methylpyridine-5-acrylic acid                                                 Lactose, U.S.P.         1000                                                  Starch, U.S.P.          300                                                   Talc, U.S.P.            65                                                    Calcium stearate        25                                                    ______________________________________                                    

The powdered mercaptomethyl compound is mixed with the starch-lactosemixture followed by the talc and calcium stearate. The final mixture isthen encapsulated in the usual manner. Capsules containing 10, 25, 50,and 100 mg. of active ingredient are also prepared by substituting 100,250, 500, and 1000 gm. for 2500 gm. in the above formulation.

3. Soft elastic capsules -- One-piece soft elastic capsules for oraluse, each containing 500 mg. of active material are prepared in theusual manner by first dispersing the powdered active material insufficient corn oil to render the material capsulatable.

4. Aqueous suspension -- An aqueous suspension for oral use containingin each 5 ml., 1 gm. of active ingredient is prepared from the followingingredients:

    ______________________________________                                                            Gm.                                                       ______________________________________                                        3-o-4α-S-benzylidine deriva-                                            tive of 2-methyl-3-hydroxy-4-                                                                       2000                                                    mercaptomethyl-5-vinylpyridine                                                Methylparaben, U.S.P. 7.5                                                     Propylparaben, U.S.P. 2.5                                                     Saccharin sodium      12.5                                                    Glycerin              3000                                                    Tragacanth powder     10                                                      Orange oil flavor     10                                                      F.D.&C. orange dye    7.5                                                     Deionized water, q.s. to 10,000 ml.                                           ______________________________________                                    

What is claimed is:
 1. A compound of structural formula: ##STR24## orpharmaceutically acceptable salt thereof wherein m is 0 or 1;R" is H orC₂ -₆ alkanoyl; A is ##STR25## or --C.tbd.C-- where R⁷ is hydrogen,chloro or fluoro; R is C₁ -₃ alkyl, hydroxy, C₂ -₆ alkanoyloxy, orhydroxy - C₁ -₃ alkyl; R¹ and R² are hydrogen or C₁ - ₃ alkyl; and R⁴ ishydrogen, C₁ -₃ alkyl, phenyl, chloro, fluoro, or carboxyl. 2.2-Methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine or pharmaceuticallyacceptable salt thereof. 3.2-Methyl-3-hydroxy-4-mercaptomethylpyridine-5-acrylic acid or apharmaceutically acceptable salt thereof. 4.2-Methyl-3-hydroxy-4-mercaptomethyl-5-(1-propenyl)pyridine or apharmaceutically acceptable salt thereof. 5.2-Methyl-3-hydroxy-4-mercaptomethyl-5-ethynylpyridine or apharmaceutically acceptable salt thereof. 6.2-Methyl-3-hydroxy-4-mercaptomethyl-5-styrylpyridine or pharmaceuticallyacceptable salt thereof.
 7. The compound of claim 1 of structuralformula: ##STR26## wherein R", A, and R⁴ have the same meaning as setforth in said claim.
 8. An anti-inflammatory composition in unit dosageform comprising a pharmaceutically acceptable inert carrier and from 5mg. to 5 gm. of a compound of structural formual: ##STR27## orpharmaceutically acceptable salt thereof wherein m is 0 or 1;R" is H orC₂ -₆ alkanoyl; A is ##STR28## or --C.tbd.C-- where R⁷ is hydrogen,chloro or fluoro; R is C₁ -₃ alkyl, hydroxy, C₂ -₆ alkanoyloxy, orhydroxy - C₁ -₃ alkyl; R¹ and R² are hydrogen or C₁ -₃ alkyl; and R⁴ ishydrogen, C₁ -₃ alkyl, phenyl, chloro, fluoro, or carboxyl.
 9. Theanti-inflammatory composition of claim 8 wherein the active ingredientis a compound of structural formula: ##STR29## wherein R", A and R⁴ havethe same meaning as set forth in said claim.
 10. The anti-inflammatorycomposition of claim 9 wherein the compound is2-methyl-3-hydroxy-4-mercaptomethy-5-vinylpyridine or pharmaceuticallyaccpetable salt thereof.
 11. The anti-inflammatory composition of claim9 wherein the compound is2-methyl-3-hydroxy-4-mercaptomethylpyridine-5-acrylic acid orpharmaceutically acceptable salt thereof.
 12. The anti-inflammatorycomposition of claim 9 wherein the compound is2-methyl-3-hydroxy-4-mercaptomethyl-5-(1-propenyl) pyridine orpharmaceutically acceptable salt thereof.
 13. The anti-inflammatorycomposition of claim 9 wherein the compound is2-methyl-3-hydroxy-4-mercaptomethyl-5-ethynylpyridine orpharmaceutically acceptable salt thereof.
 14. The anti-inflammatorycomposition of claim 9 wherein the compound is2-methyl-3-hydroxy-4-mercaptomethyl-5-styrylpyridine or pharmaceuticallyaccpetable salt thereof.
 15. A method of treating rheumatoid arthritiswhich comprises the administration, to a warm-blooded animal or human inneed of such treatment, an effective amount of a compound of structuralformula: ##STR30## or pharmaceutically acceptable salt thereof wherein mis 0 or 1;R" is H or C₂ -₆ alkanoyl; A is ##STR31## or -- C═C-- where R⁷is hydrogen, chloro or fluoro; R is C₁ -₃ alkyl, hydroxy, C₂₋₆alkanoyloxy, or hydroxy - C₁ -₃ alkyl; R¹ and R² are hydrogen as C₁ -₃alkyl; and R⁴ is hydrogen, C₁ -₃ alkyl, phenyl, chloro, fluoro, orcarboxyl.
 16. The method of claim 15 wherein the compound is ofstructural formula: ##STR32## wherein R", A, and R⁴ have the samemeaning as set forth in said claim.
 17. The method of claim 16 whereinthe compound is 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine orpharmaceutically acceptable salt thereof.
 18. The method of claim 16wherein the compound is2-methyl-3-hydroxy-4-mercaptomethylpyridine-5-acrylic acid orpharmaceutically acceptable salt thereof.
 19. The method of claim 16wherein the compound is2-methyl-3-hydroxy-4-mercaptomethy-5-(1-propenyl) pyridine orpharmaceutically acceptable salt thereof.
 20. The method of claim 16wherein the compound is2-methyl-3-hydroxy-4-mercaptomethyl-5-ethynylpyridine orpharmaceutically acceptable salt thereof.
 21. The method of claim 16wherein the compound is2-methyl-3-hydroxy-4-mercaptomethyl-5-styrylpyridine or pharmaceuticallyacceptable salt thereof.